Thromboxane B analogs

ABSTRACT

The present specification provides novel intermediates and novel processes for the synthesis of various side chain and skeletal analogs of Thromboxane B 2  (11β-homo-11a-oxa-PGF 2 α). These analogs are particularly and especially useful as reproductive cycle control agents.

BACKGROUND OF THE INVENTION

The present invention provides novel intermediates and chemicalprocesses which are useful in preparing side chain and skeletal analogsof Thromboxane B₂ (TXB₂).

Some material essential to disclosure of the present invention isincorporated here by reference from Ser. No. 676,890, filed Apr. 14,1976, now issued as U.S. Pat. No. 4,020,173, on Apr. 26, 1977, ashereinafter indicated.

Thromboxane B₂ has the structure: ##STR1## and can be considered as aderivative of thromboxanoic acid or 11a-homo-11a-oxa-prostanoic acidwhich has the following structure and carbon atom numbering: ##STR2## Asystematic name for thromboxanoic acid is7-[2β-octyltetrahydropyran-3α-yl]-heptanoic acid.

By way of comparison prostanoic acid has the structure and carbon atomnumbering ##STR3## and systematic name:7-[2β-octyl-cyclopenta-1α-yl]-heptanoic acid.

Alternatively Thromboxane B₂ is named as an analog of PGF₂.sbsb.α, i.e.,11α-homo-11a-oxo-PGF₂.sbsb.α.

In the above formulas, as well as in the formulas hereinafter given,broken line attachments to a tetrahydropyran ring or cyclopentaneindicate substituents in alpha configuration i.e., below the plane ofthe ring. Heavy solid line attachments to a tetrahydropyran ring orcyclopentane indicate substituents in beta configuration, i.e., abovethe plane of the ring. The use of wavy lines (˜) herein will representattachment of substituents in either the alpha or beta configuration orattachment in a mixture of alpha and beta configurations. See especiallythe discussion below pertaining to anomeric mixtures.

The side-chain hydroxy at C-15 in the above formula of TXB₂ is in Sconfiguration. See, Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins, which discussion applies heretowith respect to TXB₂. Expressions such as C-15, and the like, refer tothe carbon atom in the thromboxane- or prostaglandin-type compound whichis in the position corresponding to the position of the same number inthromboxanoic acid or prosanoic acid, respectively.

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) forms, i.e. thedextrorotatory and levorotatory forms. Likewise, TXB₂, which asdiscussed above is alternatively nominated as 11a-homo-11a-oxo-PGF₂α,has similar centers of asymmetry, and thus, likewise can exist inoptically active or racemic form. As drawn, the above formula representsthe particular optically active form of the TXB₂ as is obtainedbiosynthetically, for examples, as obtained by Samuelsson, Proc. Nat.Acad. Sci. USA 71, 3400-3404 (1974). The mirror image of each of theseformulas represents the other enantiomer of TXB₂. The racemic form ofTXB₂ contains equal numbers of both enantiomeric molecules, and one ofthe above formulas and the mirror image of that formula is needed torepresent correctly racemic TXB₂. For convenience hereinafter, use ofthe term, thromboxane or "TX" or "TXB" will mean the optically activeform of that thromboxane-type compound thereby referred to with the sameabsolute configuration as TXB₂ obtained biosynthetically by Samuelsson.When reference to the racemic form of a thromboxane-type compound isintended, the word "racemic" or "dl" will precede the name, e.g.,dl-TXB₂.

The term "thromboxane intermediate" as used herein, refers to anycyclopentane or tetrahydropyran derivative or acyclic compound which isuseful in preparing the various skeletal or side chain analogs of TXB₂.

When a formula, as drawn herein, is used to depict a thromboxaneintermediate each such formula represents the particular stereoisomer ofthe thromboxane intermediate which is useful in preparing the TXB analogof the same relative stereochemical configuration as TXB₂ obtainedbiosynthetically.

The term "thromboxane-type" (TX-type) product, as used herein, refers toeach of the various tetrahydropyran derivatives herein which are usefulfor at least one of the same pharmacological purposes as the TXB₂, asindicated herein.

The formulas, as drawn herein, which depict a thromboxane-type product,each represent the particular stereoisomer of the thromboxane-typeproduct which is of the same relative stereochemical configuration asTXB₂ obtained biosynthetically.

The term "thromboxane analog", as used herein, represents thatstereoisomer of a thromboxane-type product which is of the same relativestereochemical configuration as TXB₂ obtained biosynthetically or amixture comprising that stereoisomer and the enantiomer thereof. Inparticular, where a formula is used to depict a thromboxane-typecompound herein, the term thromboxane analog refers to the compound ofthat formula, or a mixture comprising that compound and the enantiomerthereof.

With respect to the asymmetric C-11 position of TXB₂ and the varioushemiacetal analogs thereof herein, the hemiacetal structure about C-11results in the presence of two diastereiomeric forms: the α-hydroxy andβ-hydroxy anomers. Dye to the mutarotation resulting from the conversionof TXB₂ or the hemiacetal analogs thereof to the hydroxy-aldehyde form,e.g. ##STR4## the 11-hydroxy represents an equilibrium mixture of alphaand beta hydroxy anomers in aqueous and certain other solutions,depicted by a ˜ OH, herein.

In formulas herein (e.g., formula IV) where a cyclopentane ortetrahydropyran ring is not present, such a ring having been cleaved orto be introduced in subsequent reaction steps, the convention by whichsubstituents about asymmetric centers are depicted as alpha or beta isas defined above, but with respect to the plane of the various atomswhich comprised said ring before its cleavage or will comprise said ringas synthesized in subsequent reaction steps. Thus, for example, informula IV the oxygen atom of the 12-hydroxy substituent, havingformerly been or successively to be the 11a-oxa of the tetrahydrofuranring is viewed as planar with C-8 to C-11 and C-12. Accordingly the C-12side chain is beta to this plane and thus rendered by a heavy solidline, while the C-12 hydrogen is alpha to this plane and thus renderedby a dotted line.

Thromboxane B₂ is known in the art. This compound is preparedbiosynthetically from arachadonic acid by B. Samuelsson, Proc. Nat.Acad. Sci. U.S.A. 71, 3400-3404 (1974). This compound alternately isnamed by him as8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid,hemiacetal or PHD.

TXB₂ is produced biosynthetically from arachadonic acid, employing thecyclic oxygenase system which is responsible for the production ofprostaglandins from arachadonic acid.

TXB₂, 15-epi-TXB₂, their 11-(lower alkyl) acetals, acceptable salts havebeen discovered to be extremely potent in causing various biologicalresponses. For that reason, these compounds (hereinafter TXB₂ compounds)have been found to be useful for pharmacological purposes.

These biological responses include:

a. stimulating smooth muscle (as shown by tests on guinea pig ileum,rabbit duodenum, or gerbil colon); and more especially and particularly

b. affecting the reproductive organs of mammals as labor inducers,abortifacients, cervical dilators, regulators of the estrus, andregulators of the menstral cycle.

Because of these biological responses, these TXB₂ compounds are usefulto study, prevent, control, or alleviate a wide variety of diseases andundesirable physilogical conditions in birds and mammals, includinghumans, useful domestic animals, pets, and zoological specimens, and inlaboratory animals, for example, mice, rats, rabbits, and monkeys.

These TXB₂ compounds, being extremely potent in causing stimulation ofsmooth muscle, are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytoxic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, these compounds for example, are useful in place of or incombination with less than usual amounts of these known smooth musclestimulators, for example, to relieve the symptoms of paralytic ileus, orto control or prevent atonic uterine bleeding after abortion ordelivery, to aid in expulsion of the placenta, and during thepuerperium. For the latter purpose, the TXB₂ compound is administered byintravenous infusion immediately after abortion or delivery at a dose inthe range about 0.01 to about 50μg. per kg. of body weight per minuteuntil the desired effect is obtained. Subsequent doses are given byintravenous, subcutaneous, or intramuscular injection or infusion duringpuerperium in the range 0.01 to 2 mg. per kg. of body weight per day,the exact dose depending on the age, weight, and condition of thepatient or animal.

The TXB₂ compounds, being useful in place of oxytocin to induce labor,are used in pregnant female animals, including man, cows, sheep, andpigs, at or near term, or in pregnant animals with intrauterine death ofthe fetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose of 0.01 to 50 μg. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks post-mature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started. An alternative route of administration isoral.

The compounds are further useful for controlling the the reproductivecycle in menstruating female mammals, including humans. Menstruatingfemale mammals are those mammals which are mature enough to menstruate,but not so old that regular menstruation has ceased. For that purposethe TXB₂ compound is administered systemically at a dose level in therange 0.01 mg. to about 20 mg. per kg. of body weight of the femalemammal, advantageously during a span of time starting approximately atthe time of ovulation and ending approximately at the time of menses orjust prior to menses. Intravaginal and intrauterine routes are alternatemethods of administration. Additionally, expulsion of an embryo or afetus is accomplished by similar administration of the compound duringthe first or second trimester of the normal mammalian gestation period.

These compounds are further useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by these compounds is useful inassisting sperm movement to the uterus. Cervical dilation bythromboxanes is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the TXB₂ compound isadministered locally or systemically.

TXB₂, for example, is administered orally or vaginally at doses of about5 to 200 mg. per treatment of an adult female human, with from one tofive treatments per 24 hour period. Alternatively TXB₂ is administeredintramuscularly or subcutaneously at doses of about one to 25 mg. pertreatment. The exact dosages for these purposes depend on the age,weight, and condition of the patient or animal.

These compounds are further useful in domestic animals as anabortifacient (especially for feedlot heifers), as an aid to estrusdetection, and for regulation or synchronization of estrus. Domesticanimals include horses, cattle, sheep, and swine. The regulation orsynchronization of estrus allows for more efficient management of bothconception and labor by enabling the herdsman to breed all his femalesin short pre-defined intervals. This synchronization results in a higherpercentage of live births than the percentage achieved by naturalcontrol. The TXB₂ compound is injected or applied in a feed at doses of0.1-100 mg. per animal and may be combined with other agents such assteroids. Dosing schedules will depend on the species treated. Forexample, mares are given the TXB₂ compound 5 to 8 days after ovulationand return to estrus. Cattle, are treated at regular intervals over a 3week period to advantageously bring all into estrus at the same time.

Certain 11-oxaprostaglandin-type compounds described above are known inthe art. See Belgian Pat. No. 830,423 (Derwent Farmdoc CPI No. 01971X)and Tetrahedron Letters 43:3715-3718 (1975).

SUMMARY OF THE INVENTION

The present specification provides novel intermediates and processes forthe production of TXB₂ and side chain and skeletal analogs of TXB₂. Inparticular, there are disclosed herein novel processes in the Chartsherein.

In particular the present specification discloses:

a. a process for preparing a thromboxane intermediate of the formula##STR5## wherein R₃₃ is alkyl of one to 4 carbon atoms, inclusive;wherein L₁ is ##STR6## wherein R₃ and R₄ are hydrogen, methyl, orfluoro, being the same or different, with the proviso that one of R₃ andR₄ is methyl only when the other is hydrogen or methyl;

wherein R₇ is ##STR7## wherein 1 is zero, one, two, or three; wherein mis one to 5, inclusive, T is alkyl of one to 3 carbon atoms, inclusive,alkoxy of one to 3 carbon atoms, inclusive, chloro, fluoro, ortrifluoromethyl, and s is one, two, or 3, the various T's being the sameor different, with the further proviso that R₇ is ##STR8## only when R₃and R₄ are hydrogen or methyl, being the same or different;

which comprises:

1. Wittig oxoalkylating a thromboxane intermediate of the formula##STR9## wherein R₃₃ is as defined above;

b. a process as in part (a) which further comprises:

2. hydrogenating the reaction product of step (1) of part (a), therebypreparing a thromboxane intermediate of the formula ##STR10## whereinR₃₃, L₁, R₇ are as defined above;

c. a process for preparing a thromboxane intermediate of the formula##STR11## wherein L₁, R₇, and R₃₃ are as defined above; wherein Y₁ istrans--CH═CH-- or --CH₂ CH₂ --; and

wherein M₅ is ##STR12## or a mixture of ##STR13## which comprises:

1. reducing and separating epimeric alcohols or alkylating a thromboxaneintermediate of the formula ##STR14## wherein R₃₃, L₁, and R₇ are asdefined above.

d. a process as in part (c) which further comprises:

2. reducing the reaction product of step (1) of part (c) to a lactol,thereby preparing a thromboxane intermediate of the formula ##STR15##wherein R₃₃, Y₁, M₅, L₁, and R₇ are as defined above;

e. a process as part (j) which further comprises:

3. reducing to a primary alcohol the reaction product of step (3) ofpart (j), thereby preparing a thromboxane intermediate of the formula##STR16## wherein R₃₃, Y₁, L₁, and R₇ are as defined above and M₆ is asdefined in part (i);

f. a process as in part (e) which further comprises:

4. ortho carboxyalkylesterifying the reaction product of step (3) part(e) hydrolyzing the ortho ester; and optionally saponifying,reesterifying, or neutralizing with base, thereby preparing athromboxane analog of the formula ##STR17## wherein g is one, two, or 3;wherein R₁ is alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl, phenyl substituted with one or two chloro, fluoro, oralkyl of one to 4 carbon atoms, inclusive, or a pharamcologicallyacceptable cation; and

wherein R₃₃, Y₁, M₆, L₁, and R₇ are as defined above;

g. a process as in part (d), which further comprises:

3. Wittig carboxyalkylating and optionally esterifying or neutralizingwith base the reaction product of step (2) of part (d), therebypreparing a thromboxane analog of the formula ##STR18## wherein R₂ ishydrogen or fluoro; and wherein g, R₁, R₃₃, Y₁, M₅, L₁, and R₇ are asdefined above.

h. a process according to part (g), which further comprises:

4. hydrogenating the cis-unsaturation of the reaction production of step(3) of part (g), thereby preparing a thromboxane analog of the formula##STR19## wherein g, R₁, and R₂, R₃₃, Y₁, M₅, L₁, and R₇ are as definedabove;

i. a process according to part (c), which further comprises:

2. etherifying the reaction product of step (1) of part (c), therebypreparing a thromboxane intermediate of the formula ##STR20## whereinR₁₀ is a blocking group; and wherein R₃₃, Y₁, M₆, L₁, and R₇ are asdefined above;

j. a process as in part (i), which further comprises:

3. reducing to a lactol the reaction product of step (2) of part (i),thereby preparing a thromboxane intermediate of the formula ##STR21##wherein M₆, R₃₃, Y₁, L₁, and R₇ are as defined above.

k. a process as in part (j), which further comprises:

4. Wittig alkylating the reaction product of step (3) of part (j),thereby preparing a thromboxane intermediate of the formula ##STR22##wherein R₈, R₃₃, Y₁, L₁, and R₇ are as defined above;

1. a process as in part (k) which further comprises:

5. primary hydroxylating the reaction product of step (4) of part (k),thereby preparing a thromboxane intermediate of the formula ##STR23##wherein M₆, R₃₃, Y₁, L₁, and R₇ are as defined above;

m. a process as in part (1), which further comprises:

6. silylating the reaction product of step (5) of part (1), therebypreparing a thromboxane intermediate of the formula ##STR24## wherein G₁is alkyl of one to 4 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, phenyl, or phenylsubstituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbonatoms, with the proviso that in the --Si(G₁)₃ moiety the various G₁ 'sare the same or different; and

wherin M₆, R₃₃, Y₁, L₁, and R₇ are as defined above.

n. a process as in part (m), which further comprises:

7. selectively oxidizing to an aldehyde the reaction product of step (6)of part (m), thereby preparing a thromboxane intermediate of the formula##STR25## wherein G₁, M₆, R₃₃, Y₁, L₁, and R₇ are as defined above.

o. a process as in part (n), which further comprises:

8. hydrolyzing the reaction product of step (7) of part (n), therebypreparing a thromboxane intermediate of the formula ##STR26## whereinM₆, R₃₃, Y₁, L₁, and R₇ are as defined above;

p. a process as in part (o), which further comprises:

9. Wittig carboxyalkylating and optionally esterifying or neutralizingwith base the reaction product of step (8) of part (o), therebypreparing a thromboxane analog of the formula ##STR27## wherein g, R₁,R₃₃, Y₁, M₅, L₁, and R₇ are as defined above;

q. a process for preparing a thromboxane analog of the formula ##STR28##wherein Z₄ is

(1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --,

(2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,

(3) cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --,

(4) --(ch₂)₃ --(ch₂)_(g) --CH₂ --,

(5) --(ch₂)₃ --(ch₂)_(g) --CF₂ --, or

(6) --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --,

wherein g is one, two, or 3;

wherein R₆ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein M₁ is ##STR29## wherein R₅ is hydrogen or methyl; wherein R₁,Y₁, L₁, and R₇ are as defined above; which comprises:

optionally dealkylacetalating and separating any mixed epimers of athromboxane analog of the formula ##STR30## wherein R₃₃, R₁, Z₄, Y₁, M₅,L₁, and R₇ are as defined above.

r. a process for preparing a thromboxane analog of the formula ##STR31##wherein Z₁, R₆, Y₁, M₁, L₁, and R₇ are as defined above;

which comprises:

reducing to a primary alcohol and optionally dealkylacetalating athromboxane analog of the formula ##STR32## wherein R₁, R₃₃, Y₁, M₁, L₁,Z₄, and R₇ are as defined above.

In particular the present specification provides in conjunction with theabove processes:

a thromboxane intermediate of the formula ##STR33## PG,26 wherein g,R₃₃, L₁, R₇, M₅, M₆, Y₁, and G₁ are as defined above.

Further the present specification discloses:

a. a process for preparing a thromboxane analog of the formula ##STR34##wherein R₃₃ is as defined above; and wherein R₃₄ is an arylmethylhydroxy-hydrogen replacing group;

which comprises:

1. reducing to a lactol a thromboxane intermediate of the formula##STR35## wherein R₃₃ and R₃₄ are as defined above;

b. a process as in part (a), which further comprises:

2. Wittig carboxylakylating and optionally esterifying the reactionproduct of step (1) of part (a), thereby preparing a thromboxaneintermediate of the formula ##STR36## wherein R₁, R₂, g, R₃₃, and R₃₄are as defined above;

c. a process as in part (b), which further comprises:

3. hydrogenating and hydrogenolyzing the reaction product of step (2) ofpart (b), thereby preparing a thromboxane intermediate of the formula##STR37## wherein R₁, R₂, g, and R₃₃ are as defined above;

d. a process according to part (c), which further comprises:

4. oxidizing to an aldehyde the primary alcohol of the reaction productof step (3) of part (c), thereby preparing a thromboxane intermediate ofthe formula ##STR38## wherein R₁, R₂, g, and R₃₃ are as defined above;

e. a process as in part (d), which further comprises:

5. Wittig oxoalkylating and optionally hydrogenating the reactionproduct of step (4) of part (d);

6. transforming the oxo moiety of the reaction product of step (5) aboveto an M₅ moiety, wherein M₅ is ##STR39## wherein R₅ is hydrogen ormethyl;

7. optionally dealkylacetalizing the reaction product of step (6) above;and

8. separating any mixed tertiary alcohol epimers of the reaction productof step (7) above;

thereby preparing a thromboxane analog of the formula ##STR40## whereinR₁, R₂, g, R₆, M₁, L₁, and R₇ are as defined above.

In particular the specification provides in conjunction with the aboveprocesses:

a thromboxane analog of the formula ##STR41## wherein R₃₃, R₃₄, R₁, R₂,and g are as defined above.

Further, the present specification discloses:

a. a process for preparing a thromboxane intermediate of the formula##STR42## wherein R₃₁ is a hydroxy-hydrogen replacing group; wherein Z₁is

1. cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --,

2. cis-Ch═CH--CH₂ --(CH₂)_(g) --CF₂ --,

3. cis--CH₂ --OH═CH--(CH₂)_(g) --CH₂ --,

4. --(ch₂)₃ (ch₂)_(g) --CH₂ --,

5. --(ch₂)₃ --(ch₂)_(g) --CF₂ --,

6. --ch₂ --o--ch₂ --(ch₂)_(g) --CH₂ --, ##STR43## wherein g is asdefined above; wherein M₃ is ##STR44## wherein R₅ is hydrogen or methyland R₃₁ is a hydroxy-hydrogen replacing group; and

wherein R₁, Y₁, L₁, and R₇ are as defined above; which comprises:

1. oxidizing with lead tetraacetate a compound of the formula ##STR45##or a mixture comprising that compound and the enantiomer thereof;wherein R₃₁, Z₁, R₁, Y₁, M₃, L₁, and R₇ are as defined above;

b. a process as in part (a) which further comprises:

2. dialkylacetalating the reaction product of step (1) of part (a),thereby preparing a thromboxane intermediate of the formula ##STR46##wherein R₃₁, R₃₃, Z₁, R₁, Y₁, M₃, L₁, and R₇ are as defined above;

c. a process as in part (b) which further comprises:

3. replacing the hydroxy hydrogen replacing groups according to R₃₁ ofthe reaction product of step (2) of part (b) with hydrogen, therebypreparing a thromboxane intermediate of the formula ##STR47## whereinR₁, Z₁, Y₁, M₁, R₇, and R₃₃ are as defined above;

d. a process for preparing a thromboxane intermediate of the formula##STR48## wherein Z₁, Y₁, M₃, L₁, and R₇ are as defined above; whichcomprises:

1. oxidizing with lead tetraacetate a compound of the formula ##STR49##or a mixture comprising that compound and the enantiomer thereof;wherein Z₁, Y₁, M₃, L₁, and R₇ are as defined above.

e. a process as in part (d) which further comprises:

2. dialkylacetalating the reaction produce of step (1) of part (d),thereby preparing a thromboxane intermediate of the formula ##STR50##wherein Z₁, R₃₃, Y₁, M₃, L₁, and R₇ are as defined above,

f. a process as in part (e), which further comprises:

3. replacing hydroxy-hydrogen replacing groups according to R₃₁ withhydrogen, thereby preparing a thromboxane intermediate of the formula##STR51## wherein Z₁, Y₁, M₁, L₁, R₇, and R₃₃ are as defined above;

g. a process for preparing a thromboxane analog of the formula ##STR52##wherein R₁, Z₁, R₃₃, Y₁, M₁, L₁, and R₇ are as defined above;

which comprises:

1. hydrolyzing a thromboxane intermediate of the formula ##STR53##wherein R₁, Z₁, R₃₃, Y₁, L₁, and R₇ are as defined above;

h. a process as in part (g), which further comprises:

2. optionally dealkylacetalating the reaction product of step (1) ofpart (g), thereby preparing a thromboxane analog of the formula##STR54## wherein R₁, R₆, Z₁, Y₁, M₁, L₁, and R₇ are as defined above;

i. a process as in part (h), which further comprises:

3. reducing to a primary alcohol the reaction product of step (2) ofpart (h), thereby preparing a thromboxane analog of the formula##STR55## wherein Z₁, Y₁, M₁, L₁, R₇, and R₆ are as defined above.

In particulaar, the specification provides, in conjunction with theabove process:

a thromboxane intermediate of the formula ##STR56## wherein R₃₁, Z₁, R₁,Y₁, M₃, L₁, R₃₃, R₆, and R₇ are as defined above.

Further the present specification discloses novel thromboxane analogs,as follows:

a. a thromboxane analog of the formula ##STR57## wherein R₆, Z₄, Y₁, M₁,L₁, and R₇ are as defined above; and

wherein X₁ is

1. --CH₂ OH, or

2. --COOR₁, wherein R₁ is as defined above; with the overall provisothat Z₁ is cis--CH═CH--(CH₂)₃ -- Y₁ is trans--CH═CH--, R₃, R₄, and R₅are all hydrogen, and R₇ is n-butyl, only when X₁ is --CH₂ OH; and

b. A thromboxane analog of the formula ##STR58## wherein Z₅ is ##STR59##and wherein g, X₁, R₆, Y₁, M₁, L₁, and R₇ are as defined above.

Within the scope of the novel thromboxane analogs of this specification,thre are represented TXB-type compounds by virtue of the tetrahydropyranring structure common to each of these thromboxane analogs: ##STR60## or11-deoxy-11α- or 11β-alkoxy-TXB-type compounds (e.g., TXB-type, 11-alkylacetals) by virtue of the tetrahydropyran ring structure common to eachof these thromboxane analogs: ##STR61## wherein R₃₃ is alkyl of one to 4carbon atoms, inclusive.

Those analogs herein wherein Z₄ is cis--CH═CH--CH₂ --(CH₂)_(g) -- CH₂ --or cis--CH═CH--(CH₂ --(CH₂)_(g) --CF₂ -- are named as "TXB₂ " compounds.The latter compounds are further characterized as 2,2-difluoro-TXB₂-type compounds. When g is 2 or 3, the prostaglandin analogs sodescribed are "2a-homo" or "2a,2b-dihomo" compounds, since in this eventthe carboxy terminated side chain contains 8 or 9 carbon atoms,respectively, in place of the 7 carbon atoms contained in TXB₂. Theseadditional carbon atoms are considered as though they were insertedbetween the C-2 and C-3 positions. Accordingly, these additional carbonatoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3position.

Further when Z₄ is --(CH₂)₃ --(CH₂)_(g) --CH₂ -- or --(CH₂)₃ --(CH₂)_(g)--CF₂, wherein g is as defined above, the compounds so described are"TXB₁ " compounds. When g is 2 or 3, the "2a-homo" and "2a,2b-dihomo"compounds are described as is discussed in the preceding paragraph.

When Z₄ is --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ -- the compounds sodescribed are named as "5-oxa-TXB₁ " compounds. When g is 2 or 3, thecompounds so described are "2a-homo" or "2a,2b-dihomo" compounds,respectively, as discussed above.

When Z₄ is cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --, wherein g is as definedabove, the compounds so described are named "cis-4,5-didehydro-TXB₁ "compounds. When g is 2 or 3, the compounds so described are furthercharacterized as "2a-homo" or "2a,2b-dihomo" compounds, respectively, asdiscussed above.

For the novel compounds of this invention wherein Z₅ is ##STR62## thereare described, respectively, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-or 3,7-inter-m-phenylene-4,5,6-trinor-TXB₁ -type compounds, when g is 1.When g is 2 or 3, the above compounds are additionally described as"2a-homo" or "2a,2b-dihomo" TXB-type compounds, respectively.

The novel thromboxane analogs of this invention wherein Y₁ is --CH₂ CH₂-- are referred to as "13,14-dihydro" compounds.

When R₇ is --(CH₂)_(m) --CH₃, wherein m is as defined above, thecompounds so described are named as "19,20-dinor", "20-nor","20-methyl", or "20-ethyl" compounds when m is one, 2, 4, or 5,respectively.

When R₇ is ##STR63## wherein T and s are as defined above, the compoundsso described are named as "16-phenyl-17,18,19,20-tetranor" compounds,when s is 0. When s is one, 2, or 3, the corresponding compounds arenamed as "16-(substituted phenyl)-17,18,19,20-tetranor" compounds.

When R₇ is ##STR64## wherein T and s are as defined above, tne compoundsso described are named as "17-phenyl-18,19,20-trinor" compounds, when sis 0. When s is one, 2, or 3, the corresponding compounds are named as"17-(substituted phenyl)18,19,20-trinor" compounds.

When R₇ is ##STR65## wherein T and s are as defined above, the compoundsso described are named as "18,-phenyl-19,20-dinor" compounds, when s is0. When s is one, 2, or 3, the corresponding compounds are named as"18-(substituted phenyl)-19,20-dinor" compounds.

When R₇ is ##STR66## wherein T and s are as defined above, the compoundsso described are named as "19-phenyl-20-nor" compounds, when s is 0.When s is one, 2, or 3, the corresponding compounds are named as"19-(substituted phenyl)-20-nor" compounds.

When R₇ is ##STR67## wherein T and s are as defined above, and neitherR₃ nor R₄ is methyl, the compounds so described are named as"16-phenoxy-17,18,19,20-tetranor" compounds, when s is zero. When s isone, 2, or 3, the corresponding compounds are named as "16-(substitutedphenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R₃and R₄ is methyl or both R₃ and R₄ are methyl, then the correspondingcompounds wherein R₇ is as defined in this paragraph are named as"16-phenoxy or 16-substituted phenoxy)-18,19,20-trinor" compounds or"16-methyl-16-phenoxy- or 16-(substituted phenoxy)-18,19,20-trinor"compounds, respectively.

When at least one of R₃ and R₄ is not hydrogen then (except for the16-phenoxy compounds discussed above) there are described the"16-methyl" (one and only one of R₃ and R₄ is methyl), "16,16-dimethyl"(R₃ and R₄ are both methyl), "16-fluoro" (one and only one of R₃ and R₄is fluoro), "16,16-difluoro" (R₃ and R₄ are both fluoro) compounds. Forthose compounds wherein R₃ and R₄ are different, the thromboxane analogsso represented contain an asymmetric carbon atom at C-16. Accordingly,two epimeric configurations are possible: "(16S)" and "(16R)". Further,there is described by this invention the C-16 epimeric mixture:"(16RS)".

When R₅ is methyl, the compounds so described are named as "15-methyl"compounds. When R₆ is alkyl, the compounds so described are named asTXB-type, 11α- or 11β-alkyl acetals or preferably, as described above,as "11-deoxy-11α- or 11β-alkoxy-TXB" compounds.

There is further provided by this invention both epimeric configurationsof the hydroxy at C-15. As discussed herein, TXB₂, as obtainedbiosynthetically has the "S" configuration at C-15. Further, as drawnherein TXB₂, as obtained biosynthetically, has the 15-hydroxy moiety inthe "alpha" configuration. Further, 15-epi-TXB₂, by the convention usedfor drawing the thromboxane analogs herein, has the 15-hydroxysubstitutent in the beta configuration. Thus, the novel thromboxaneanalogs disclosed herein wherein the 15-hydroxy has the same absoluteconfiguration as 15-epi-TXB₂ at C-15 will be named "15-epi" compounds.When the designation "15-epi" is absent, those compounds wherein theconfiguration of the 15-hydroxy is the same as the absoluteconfiguration of TXB₂, i.e. the 15α-hydroxy configuration.

When X₁ is --CH₂ OH the thromboxane analogs so described are named as"2-decarboxy-2-hydroxymethyl" compounds.

Accordingly, as indicated by the preceeding paragraphs, the novel PGanalogs disclosed herein are named according to the system described inNelson, N.A., J. Med. Chem. 17, 911 (1974).

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, and isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2.3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl,2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl,3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthylmethyl).

Examples of phenyl substituted by one of 3 chloro or alkyl of one to 4carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of ##STR68## wherein T is alkyl of one to 3 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or alkoxy of one to 3 carbonatoms, inclusive; and s is zero, one, 2, or 3, with the proviso that notmore than two T's are other than alkyl, are phenyl, (o-, m-, orp-)tolyl, (o-, m-, or p-)-ethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl,5-ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o-, m-, orp-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-,2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl,2-fluoro-(o-, m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-,3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)-chlorophenyl,2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-tolyl,4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl,(2,3- 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyl,4-chloro-3-fluorophenyl, (3 - or 4-) chloro-2-fluorophenyl, o-, m-, orp-trifluoromethylphenyl, (o-, m-, or p-)methoxyphenyl, (o-, m-, orp-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dichloro(5-or 6-)methylphenyl.

The novel thromboxane analogs disclosed herein correspond to the TXBcompounds described above, in that the novel thromboxane analogs exhibitTXB₂ -like activity.

Specifically the TXB analogs disclosed herein correspond to the TXB₂described above, in that these TXB analogs are useful for theabove-described purposes for which the TXB₂ is used, and are used in thesame manner as TXB₂, as described above. TXB₂ is potent in causingbiological responses even at low doses. Moreover, for the aboveapplications, TXB₂ exhibits an inconveniently short duration ofbiological activity. In striking contrast, the novel thromboxane analogsof this invention are substantially more selective with regard topotency in causing TXB₂ -like biological responses, and have asubstantially longer duration of biological activity. Accordingly, eachof these novel thromboxane analogs is surprisingly and unexpectedly moreuseful than TXB₂ for at least one of the pharmacological purposesindicated above for the latter, because it has a different and narrowerspectrum of biological potency than TXB₂ and therefore is more specificin its activity and causes smaller and fewer undesired side effects thanwhen TXB₂ is used for the same purpose. Moreover, because of itsprolonged activity, fewer and smaller doses of the novel thromboxaneanalog are frequently effective in attaining the desired result.

Another feature of the novel thromboxane analogs disclosed herein,especially the preferred TXB analogs defined hereinbelow is that thesenovel TXB analogs logs are administered effectively orally,sublingually, intravaginally, buccally, or rectally. These routes ofadministration are advantageous because they facilitate maintaininguniform levels of these compounds in the body with fewer, shorter, orsmaller doses, and make possible self-administration by the patient.

Accordingly, the novel thromboxane analogs of this invention areadministered in various ways for various purposes: e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intraveneous injection of infusion, sterileaqueous isotonic solutions are preferred. For intravenous injection orinfusion, sterile aqueous isotonic solutions are preferred. For thatpurpose it is preferred because of increased water solubility that whenX₁ is --COOR₁, R₁ be hydrogen or a pharmacologically acceptable cation.For subcutaneous or intramuscular injection, sterile solutions orsuspensions of the acid, salt, or ester form in aqueous or non-aqueousmedia are used. Tablets, capsules. and liquid preparations such assyrups, elixirs, and simple solutions, with the usual pharmaceuticalcarriers are used for oral sublingual administration. For rectal orvaginal administration, suppositories prepared as known in the art areused. For tissue implants, a sterile tablet or silicone rubber capsuleor other object containing or impregnated with the substance is used.

The novel TXB analogs of this invention are used for the purposesdescribed above as primary alcohols or in the free acid form (X₁ is--COOH), in ester form or in pharmacologically acceptable salt form.When the ester form is used, the ester is any of those within the abovedefinition of R₁. However, it is preferred that the ester be alkyl ofone to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethylare especially preferred for optimum absorption of the compound by thebody or experimental animal system; and straight-chain octyl, nonyl,decyl, undecyl, and dodecyl are especially preferred for prolongedactivity in the body or experimental animal.

Pharmacologically acceptable salts of the novel prostaglandin analogs ofthis invention compounds useful for the purposes described above arethose with pharmacologically acceptable metal cations, ammonium, aminecations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and the like aliphatic,cycloaliphatic, araaliphatic amines containing up to and including about18 carbon atoms, as well as heterocyclic amines, e.g., piperidine,morpholine, pyrrolidine, piperazine, and lower-alkyl derivativesthereof, e.g., 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine,N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like. Further useful amine salts are thebasic amino acid salts, e.g., lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope ofthis invention are preferred.

It is preferred that g be one or 3, and especially preferred that g beone, i.e., the natural chain length of TXB₂. Further when the other sidechain contains --(CH₂)_(m) --CH₃, it is preferred that m be 3. For thosecompounds wherein R₇ is ##STR69## it is preferred that s and l be zeroor one and T be chloro, fluoro, or trifluoromethyl.

For those compounds wherein at least one of R₃ and R₄ is methyl orfluoro, it is preferred that R₅ be hydrogen. For those compounds whereinR₅ is methyl, it is preferred that R₃ and R₄ both be hydrogen. For thosecompounds wherein R₇ is ##STR70## it is preferred that R₃, R₄, R₅, andR₆ all be hydrogen.

It is further preferred that the 15-hydroxy not be of the 15-epiconfiguration, i.e., that the hydroxy be in the alpha configuration whenthe formulas are as drawn herein.

Especially preferred are those compounds which satisfy two or more ofthe above preferences. Further, the above preferences are expresslyintended to describe the preferred compounds within the scope of anygeneric formula of novel thromboxane analogs disclosed herein.

In another aspect of the interpretation of the preferences herein, thevarious thromboxane tetrahydropyran ring structures (e.g. hemiacetal and11α- or 11β-alkyl acetals) as employed herein are each representative ofa particular "parent structure" which is useful in naming andcategorizing the novel thromboxane analogs disclosed herein. Further,where a formula depicts a genus of TXB analogs disclosed hereinevidencing a single tetrahydropyran ring structure, then eachcorresponding genus of TXB analogs evidencing one of the remainingtetrahydropyran ring structures cited herein for novel thromboxaneanalogs is intended to represent an equally preferred genus ofcompounds. Thus, for example, for each genus of TXB-type productsdepicted by a formula herein, the corresponding genus of11-deoxy-11α-methoxy-TXB₂ -type products are equally preferredembodiments of present disclosure as the genus of TXB-type products.

Finally where subgeneric group of TXB analogs of any tetrahydropyranring structure are described herein, then the corresponding subgenericgroups of TXB analogs of any other tetrahydropyran ring structure isintended to represent equally preferred embodiments of the presentinvention.

The Charts herein described methods whereby the novel thromboxaneanalogs of this invention are prepared.

With respect to the charts R₁, R₂, R₆, R₁₀, R₇, R₃₁, R₃₃, R₃₄, M₁, M₃,M₅, M₆, L₁, Y₁, X₁, Z₄, Z₅, G₁, m, and g are as defined above. ##STR71##

R₉ is an acyl protecting group.

Z₁ is Z₄ or Z₅, Z₃ is oxa or methyl. Z₇ is R₃₆ -B wherein R₃₆ is alkylor aryl, preferably such that the corresponding boranic acid is readilyavailable, e.g., (n-butyl)-boronic acid or phenylboronic acid.

R₉ is an acyl protecting group. Acyl protecting groups according to R₉,include:

a. benzoyl;

b. benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms,inclusive, phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro,with the proviso that not more than 2 substituents are other than alkyl,and that the total number of carbon atoms in the substituents does notexceed 10 carbon atoms, with the further proviso that the substituentsare the same or different;

c. benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms,inclusive;

d. naphthoyl;

e. naphthoyl substituted with one to 9, inclusive alkyl of one to 4carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive,or nitro, with the proviso that not more than 2 substituents on eitherof the fused aromatic rings are other than alkyl and that the totalnumber of carbon atoms in the substituents on either of the fusedarmoatic rings does not exceed 10 carbon atoms, with the further provisothat the various substituents are the same or different; or

f. alkanoyl of 2 to 12 carbon atoms, inclusive.

In preparing these acyl derivatives of a hydroxy-containing compoundherein, methods generally known in the art are employed. Thus, forexample, an aromatic acid of the formula R₉ OH, wherein R₉ is as definedabove (e.g., benzoic acid), is reacted with the hydroxy-containingcompound in the presence of a dehydrating agent, e.g. p-toluenesulfonylchloride or dicyclohexylcarbodiimide; or alternatively an anhydride ofthe aromatic acid of the formula (R₉)₂ O (e.g., benzoic anhydride) isused.

Preferably, however, the process described in the above paragraphproceeds by use of the appropriate acyl halide, e.g., R₉ Hal, whereinHal is chloro, bromo, or iodo. For example, benzoyl chloride is reactedwith the hydroxyl-containing compound in the presence of a hydrogenchloride scavenger, e.g. a tertiary amine such as pyridine,triethylamine or the like. The reaction is carried out under a varietyof conditions, using procedures generally known in the art. Generallymild conditions are employed: 0°-60° C., contacting the reactants in aliquid medium (e.g., excess pyridine or an inert solvent such asbenzene, toluene, or chloroform). The acylating agent is used either instoichiometric amount or in substantial stoichiometric excess.

As examples of R₉, the following compounds are available as acids (R₉OH), anhydrides ((R₉)₂ O), or acyl chlorides (R₃ Cl): benzoyl;substituted benzoyl, e.g., 2-, 3-, or 4-)-methylbenzoyl, (2-, 3-, or4-)-ethyl benzoyl, (2-, 3-, or 4-)-isopropylbenzoyl (2-, 3-, or4-)-tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl,2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl,alphaphenyl-(2-, 3-, or 4-)-toluyl, (2-, 3-, or 4-)-phenethylbenzoyl,(2-, 3-, or 4-)-nitrobenzoyl, (2,4-, 2,5-, or 2,3-)-dinitrobenzoyl,2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterifiedphthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl,substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)-methyl-1-naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl,4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl,8benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl,4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 8-)methyl-1-naphthoyl,4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-naphthoyl; and acetyl.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoylchloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R₉ Cl compoundscorresponding to the above R₉ groups. If the acyl chloride is notavailable, it is prepared from the corresponding acid and phosphoruspentachloride as is known in the art. It is preferred that the R₉ OH,(R₉)₂ O, or R₉ Cl reactant does not have bulky hindering substituents,e.g. tert-butyl on both of the ring carbon atoms adjacent to thecarbonyl attaching site.

The acyl protecting groups, according to R₉, are removed by deacylation,Alkali metal carbonate or hydroxide are employed effectively at ambienttemperature for this purpose. For example, potassium carbonate orhydroxide in aqueous methanol at about 25° C. is advantageouslyemployed.

Those blocking groups within the scope of R₁₀ are any group whichreplaces a hydroxy hydrogen and is neither attacked by nor as reactiveto the reagents used in the transformations used herein as an hydroxy isand which is subsequently replaceable with hydrogen in the preparationof the prostaglandin-type compounds. Several blocking groups are knownin the art, e.g. tetrahydropyranyl and substituted tetrahydropyranyl.See for reference E. J. Corey, Proccedings of the Robert A WelchFoundation Conferences on Chemical Research, 12, Organic Synthesis, pgs.51-79 (1969). Those blocking groups which have been found usefulinclude:

a. tetrahydropyranyl;

b. tetrahydrofuranyl; and

c. a group of the formula

    --C(OR.sub.11) (R.sub.12)--CH(R.sub.13) (R.sub.14),

wherein R₁₁ is alkyl of one to 18 carbon atoms inclusive, cycloalkyl of3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl or phenyl substituted with one to 3 alkyl of one to 4carbon atoms, inclusive, wherein R₁₂ and R₁₃ are alkyl of one to 4carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3alkyl of one to 4 carbon atoms, inclusive, or when R₁₂ and R₁₃ are takentogether --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c), wherein a is 3,4, or 5, or b is one, 2, or 3, and c is one, 2, or 3, with the provisothat b plus c is 2, 3, or 4, with the further proviso that R₁₂ and R₁₃may be the same or different, and wherein R₁₄ is hydrogen or phenyl.

When the blocking group R₁₀ is tetrahydropyranyl, the tetrahydropyranylether derivative of any hydroxy moieties of the TXB-type intermediatesherein is obtained by reaction of the hydroxy-containing compound with2,3-dihydropyran in an inert solvent, e.g. dichloromethane, in thepresence of an acid condensing agent such as p-toluenesulfonic acid ofpyridine hydrochloride. The dihydropyran is used in large stoichiometricexcess, preferably 4 to 100 times the stoichiometric amount. Thereaction is normally complete in less than an hour at 20° to 50° C.

When the blocking group is tetrahydrofuranyl, 2,3-dihydrofuran is used,as described in the preceding paragraph, in place of the2,3-dihydropyran.

When the blocking group is of the formula

    --C(OR.sub.11) (R.sub.12)--CH(R.sub.13) (R.sub.14),

wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above, the appropriatereagent is a vinyl ether, e.g. isobutyl vinyl ether or any vinyl etherof the formula

    C(OR.sub.11) (R.sub.12)═C(R.sub.13) (R.sub.14),

wherein R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above; or an unsaturatedcyclic or heterocyclic compound, e.g. 1-cyclohexen-1-yl methyl ether, or5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese, et al., Journal of theChemical Society 89, 3366 (1967). The reaction conditions for such vinylethers and unsaturated compounds are similar to those for dihydropyranabove.

The blocking groups according to R₁₀ are removed by mild acidichydrolysis. For example, by reaction with (1) hydrochloric acid inmethanol; (2) a mixture of acetic acid, water, and tetrahydrofuran, or(3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran,at temperatures below 55° C., hydrolysis of the blocking groups isachieved.

R₃₄ is an arylmethyl hydroxy-hydrogen replacing group, which is definedas any arylmethyl group which replaces the hydroxy hydrogen of theintermediates in the preparation of the various thromboxane analogsherein which is subsequently replaceable by hydrogen in the processesherein for preparation of these respective thromboxane analogs, beingstable with respect to the various reactions to which R₃₄ -containingcompounds are subjected and being introduced and subsequently removed byhydrogenolysis under conditions which yield substantially quantitativeyields of desired products.

Examples of arylmethyl hydroxy-hydrogen replacing groups are

a. benzyl (i.e., ##STR72##

b. benzyl substituted by one to 5 alkyl of one to 4 carbon atoms,inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different;

c. benzhydryl (i.e., ##STR73##

d. benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms,inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different on each of the aromatic rings;

e. trityl (i.e., ##STR74##

f. trityl substituted by one to 15 alkyl of one to 4 carbon atoms,inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different on each of the aromatic rings.

The introduction of such ether linkages to the hydroxy-containingcompounds herein, particularly the benzyl or substituted benzyl etherproceeds by methods known in the art, for example by reaction of thehydroxy-containing compound with the benzyl or substituted benzyl halide(chloride, bromide, or iodide) corresponding to the desired ether. Thisreaction proceeds in the presence of an appropriate condensing agent(e.g., silver oxide). The mixture is stirred and heated to 50°-80° C.Reaction times of four to 20 hours are ordinarily sufficient.

These arylmethyl grops are subsequently removed by hydrogenolysis, forexample by catalytic hydrogenation over a 5-10 percentpalldium-on-carbon catalyst.

R₃₁ is a hydroxy-hydrogen replacing group which is stable to thereagents employed herein in the preparation of TXB₂, and subsequently,readily hydrolyzed or hydrogenolysed as required herein. Thosehydroxy-hydrogen replacing groups useful for this purpose include ayacyl protecting group according to R₉, blocking group according to R₁₀,or arylmetyl hydroxy-hydrogen replacing group according to R₃₄.

Various reactions in the succeeding charts introduce silyl groups of theformula --Si(G₁)₃. In some cases, such silylations are general, in thatthey silylate all hydroxyls, while in other cases they are selective, inthat while one or more hydroxyls are silylated, at least one otherhydroxyl remains unaffected. For any of these silylations, silyl groupswithin the scope of --Si(G₁)₃ include trimethylsilyl,dimethylphenylsilyl, triphenylsilyl, t-butyldimethylsilyl, ormethylphenylbenzylsilyl. With regard to G₁, examples of alkyl aremethyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl,and the like. Examples of aralkyl are benzyl, phenethyl, α-phenylethyl,3-phenylpropyl, α-naphthylmethyl, and 2-(β-naphthyl)-ethyl. Examples ofphenyl substituted with halo or alkyl are p-chlorophenyl,m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

These silyl groups are known in the art. See for example, Pierce"Silylation of Organic Compounds," Pierce Chemical Company, Rockford,Ill. (1968). When silylated products of the charts below are intended tobe subjected to chromatographic purification, then the use of silylgroups known to be unstable to chromatography (e.g. trimethylsilyl)should be avoided. Further, when silyl groups are to be introducedselectively, silylating agents which are readily available and known tobe useful in selective silylations are employed. For example,trimethylsilyl, triphenylsilyl and t-butyldimethylsilyl groups areemployed when selective introduction is required. Further, when silylgroups are to be selectively hydrolyzed over protecting groups accordingto R₁₀ or acyl protecting groups, then the use of silyl groups which arereadily available and known to be easily hydrolyzable withtetra-n-butylammonium fluoride are employed. A particularly useful silylgroup for this purpose is t-butyldimethylsilyl, although other silylgroups (e.g. trimethylsilyl) are likewise employed.

With respect to Chart A (Part I) the formula XI compound is prepared asdescribed in U.S. Pat. No. 4,020,173. This compound is available ineither of two enantiomeric forms or as a mixture thereof.

The formula XII compound is prepared from the formula XI compound by aWittig alkylation. Reagents known in the art of prepared by methodsknown in the art are employed. The transenone lactone is obtainedstereospecifically. See for reference D. H. Wadsworth, et al., Journalof Organic Chemistry 30, 680 (1965).

In the preparation of the formula XII compound, certain phosphonates areemployed in the Wittig reaction. These phosphonates are of the generalformula ##STR75## wherein L₁ and R₇ are as defined above and R₁₅ isalkyl of one to 8 carbon atoms, inclusive.

Phosphonates of the above general formula are prepared by methods knownin the art. See Wadsworth, et al. as cited above.

Conveniently the appropriate aliphatic acid ester is condensed with theanion of dimethyl methylphosphonate as produced using n-butyllithium.For this purpose, acids of the general formula ##STR76## are employed inthe form of their lower alkyl esters, preferably methyl or ethyl. Themethyl esters for example are readily obtained by reaction of thecorresponding acids with diazomethane.

For example, when R₇ is ##STR77## wherein T and s are as defined above,and R₃ and R₄ of the L₁ moiety are both hydrogen, the correspondingphenoxy or substituted phenoxy acetic acids are known in the art orreadily available in the art. Those known in the art include thosewherein the R₇ moiety is: phenoxy, (o-, m-, or p-)tolyloxy-, (o-, m-, orp-)ethylphenoxy-, 4-ethyl-o-tolyloxy-, (o-, m-, or p-)propylphenoxy-,(o-, m-, or p-)-t-butylphenoxy-, (o-, m-, or p-)fluorophenoxy-,4-fluoro-2,5-xylyloxy-, (o-, m-, or p-) chlorophenyoxy-, (2,3-, 2,4-,2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenoxy-, (o-, m-, orp-)trifluoromethylphenoxy-, or (o-, m-, or p-)methoxyphenoxy-.

Further, many 2-phenoxy- or substituted phenoxy propionic acids arereadily available, and are accordingly useful for the preparation of theacids of the above formula wherein one and only one of R₃ and R₄ of theL₁ moiety is methyl and R₇ is phenoxy or substituted phenoxy. These2-phenoxy or 2-substituted phenoxy propionic acids include those whereinthe R₇ moiety is p-fluorophenoxy-, (o-, m-, or p-)chlorophenoxy-, (2,3-,2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenoxy-, (4- or6-chloro-o-tolyloxy-, phenoxy-, (o-, m-, or p-)tolyloxy, 3,5-xylyloxy-,or m-trifluoromethylphenoxy-.

Finally there are available many 2-methyl- 2-phenoxy- or(2-substituted)phenoxypropionic acids, which are useful in thepreparation of the above acids wherein R₃ and R₄ of the L₁ moiety areboth methyl and R₇ is phenoxy or substituted phenoxy. These2-methyl-2-phenoxy-, or (2-substituted)phenoxypropionic acids includethose wherein R₇ is: phenoxy-, (o-, m-, or p-) chlorophenoxy-, (2,3-,2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenoxy-.

Other phenoxy substituted acids are readily available by methods knownin the art, for example, by Williamson synthesis of ethers using anα-halo aliphatic acid or ester with sodium phenoxide or a substitutedsodium phenoxide. Thus, the (T)_(s) -substituted sodium phenoxide isreacted with, for example, the α-chloro aliphatic acid, or the alkylester derivative thereof, with heating to yield the acid of the abovegeneral formula, which is recovered from the reaction mixture byconventional purification techniques.

There are further available phenyl substituted acids of the aboveformula wherein R₇ is phenyl, benzyl, phenylalkyl, or substitutedphenyl, benzyl, or phenylalkyl.

For example, when 1 is one and R₃ and R₄ of the L₁ moiety are bothhydrogen, there are available the following phenyl or substituted phenylpropionic acids: (o-, m-, or p-)-chlorophenyl-, p-fluorophenyl-,m-trifluoromethylphenyl-, (o-, m-, or p-)methylphenyl-, (o-, m-, orp-)methoxyphenyl-, (2,4-, 2,5-, or 3,4-)dichlorophenyl-, (2,3- 2,4-,2,5-, 2,6-, or 3,4-)dimethylphenyl-, or (2,3-, 2,4-, 2,5-, 2,6-, 3,4-,or 3,5-)dimethoxyphenyl-.

When one and only one or R₃ and R₄ of the L₁ moiety is methyl and 1 isone, there are available, for example, the following 2-methyl-3-phenylor substituted phenyl propionic acids: phenyl, o-chlorophenyl-, (o-, orp-)methylphenyl-, (o-, m-, or p-)methoxy-m (2,4- or3,4-)difluorophenyl-, 2,3-dimethylphenyl-, and (2,3-, 3,4-, or4,5-)dimethoxyphenyl-.

When both R₃ and R₄ are methyl and 1 is one, there are available, forexample, the following 2,2-dimethyl-3-phenyl or substituted phenylpropionic acids: phenyl- and p-methylphenyl.

When one and only one of R₃ and R₄ is fluoro and 1 is one, there isavailable, for example, 2-fluoro-3-phenyl propionic acid.

Phenyl substituted acids (as above wherein R₇ is aralkyl) are availableby methods known in the art, for example, by reacting a mixture of theappropriate methyl- or fluoro-substituted acetic acid, with a solutionof a secondary amine (e.g., diisopropylamine), and n-butyllithium in anorganic diluent (e.g., tetrahydrofuran) with the appropriatelysubstituted benzyl chloride. Thus, the above acid is obtained by thefollowing reaction (when 1 is not zero); ##STR78## The above reactionproceeds smoothly, ordinarily at 0° C. The product acid is recoveredusing conventional methods.

For the acids of the above formula wherein R₇ is n-alkyl, many suchacids are readily available.

For example, when R₃ and R₄ of the L₁ moiety are both hydrogen there areavailable butyric, pentanoic, hexanoic, heptanoic, and octanoic acids.

For example, when and only one of R₃ and R₄ of the L₁ moiety is methyl,there are available the following 2-methyl alkanoic acids: butyric,pentanoic, hexanoic, heptanoic, and octanoic.

For example, when one of R₃ and R₄ of the L₁ moiety is fluoro there areavailable the following 2-fluoro alkanoic acids: butyric, pentanoic,hexanoic, heptanoic, and octanoic.

The acids of the above general formula wherein R₇ is alkyl and R₃ and R₄of the L₁ moiety are fluoro are conveniently prepared from thecorresponding 2-oxo-alkanoic acids, i.e. butyric, pentanoic, hexanoic,heptanoic, and octanoic. The transformation of these 2-oxo-alkanoicacids to the corresponding 2,2-difluoro alkanoic acids proceeds bymethods known in the art, using known ketonic fluorinating reagents. Forexample, MoF₆.BF₃ is advantageously employed in the fluorination.

The formula XII compound is transformed to the formula XIII compound bycatalytic hydrogenation. For example, conventional methods forhydrogenation of unsaturated prostanoic acid derivatives are employed.Thus a 5-10 percent palladium-on-carbon catalyst at low pressure (aboveor near atmospheric) is employed.

The formula XIV compound is prepared from the formula XII or XIII 3-oxobicyclic acetal lactone by transformation of the 3-oxo-moiety to the M₅moiety.

The above 3-oxo bicyclic acetal lactone is transformed to thecorresonding 3α or 3β-hydroxy bicyclic acetal lactone, wherein M₅ is##STR79## by reduction of the 3-oxo moiety, followed by optionalseparation of the 3α- and 6β-hydroxy epimers. For this reduction theknown ketonic carbonyl reducing agents which do not reduce ester or acidgroups or carbon-carbon double bonds (when such reduction isundesirable) are employed. Examples of these agents are the metalborohydrides, especially sodium, potassium, and zinc borohydrides,lithium(tri-tert-butoxy)-aluminum hydride, metal trialkyl borohydrides,e.g. sodium trimethoxy borohydride, lithium borohydride, and the like.In those cases in which carbon-carbon double bond reduction need not beavoided, the boranes, e.g. disiamylborane (bis-3-methyl-2-butyl borane)are alternatively employed.

For the production of C-15 epimerically pure prostaglandins, the 15-epicompound is separated from the mixture by methods known in the art. Forexample, silica gel chromatography is advantageously employed.

The 3-oxo bicyclic acetal lactone is transformed into the corresponding(3RS)-3-methyl bicyclic acetal lactone wherein M₅ is a mixture of##STR80## by reaction of the 3-oxobicyclic acetal lactone with aGrignard reagent, CH₃ MgHal, wherein Hal is chloro, bromo, or iodo. TheGrignard complex is thereafter hydrolyzed, for example, using saturatedaqueous ammonium chloride as is known in the art. An alternate methodfor transforming the 3-oxo compound to a 3(RS)-3-methyl compound is byreaction of the 3-oxo bicyclic acetal lactone with trimethylaluminum.

The preferred method for separation of these (3RS)-3-methyl epimers isby separation of the corresponding C-15 epimers of the TXB-type, methylesters using silica gel chromatography or high pressure liquidchromatography (HPLC). The formula XV compound is then prepared from theformula XI compound by reduction of the formula XIV acetal lactone to anacetal lactol. Methods known in the art are employed. For example,diisobutylaluminum hydride is employed at -60° to -78° C.

Chart A (Part II) provides a method whereby the formula XVI compound asprepared in Chart A (Part I) is transformd to acis-4,5-didehydro-thromboxane analog according to formula XXIV. Withrespect to Chart A (Part II) the formula XVII compound is prepared fromthe formula XVI compound by etherifying the free hydroxyl. Thisetherification proceeds by methods described above for the introductionof blocking groups according to R₁₀. Thereafter, the formula XVIIcompound so produced is transformed to the corresponding lactol offormula XVIII employing diisobutyl aluminum hydride, as discussed above.

The formula XIX compound is then prepared from the formula XVIIIcompound employing methods known in the art. For example, thetransformation of γ-lactols to corresponding prop-1-enyl, compounds asdescribed in U.S. Pat. No. 3,920,327. In particular, see the discussionrelating to Chart O of this patent. Thus, the formula XVIII lactol isreacted with methylenetriphenylphosphorane or methyltriphenylphosphoniumbromide. The latter reaction proceeds as is generally known in the art,by first mixing the methyltriphenylphosphonium bromide with sodiodimethylsulfinylcarbanide, at ambient temperature, and thereafter addingthe formula XVIII lactol.

The formula XIX compound is then converted to the corresponding formulaXX or primary alcohol by methods known in the art, for example, as inthe above cited U.S. Pat. No. 3,920,723 (see the discussion pertainingto Chart O). Thus, hydroboration effects this transformation.

Thereafter, the formula XX compound is transformed to correspondingformula XXI compound by silylation of both the primary and secondaryalcohols of the formula XX compound. For this purpose trimethylsilyl isan especially preferred silylating group. The use of a especially stablesilyl group (e.g. t-butyldimethylsilyl) should be avoided. Thereafterthis formula XXI silylated compound is oxidized to the correspondingaldehyde, employing methods described in U.S. Pat. No. 4,020,173. See,for example, the discussion pertaining to Chart A therein, particularlythe transformation of the formula XXX to formula XXXI compound. Thus,for this purpose the Collins reagent is employed by methods known in theart. See R. Ratcliffe, et al., Journal of Organic Chemistry, 35, 4000(1970).

This formula XXII aldehyde is first hydrolyzed to the formula XXIIlactol and then transformed to the formula XXIV compound by a Wittigcarboxyalkylation. Accordingly, the appropriate (ω-carboxyalkyl)triphenylphosphonium bromide is employed, as described above. When R₁ isnot hydrogen, the preparation of the formula XXIV compound additionallyrequires esterification of the free acid produced by the Wittigalkylation. Procedures and methods for accomplishing this esterificationare described below.

By the procedure of Chart A (Part III), the formula XXV lactol istransformed to the corresponding formula XXVII 5-oxa-11-deoxy-11α- or11β-alkoxy-TXB₁ -type compound. First the formula XXVI compound isobtained by reduction of the formula XXV lactol, for example, withaqueous methanolic or ethanolic sodium borohydride to the formula XXVIcompound. Alternatively, and preferably, the formula XXVI compound isobtained by a one step reduction of the formula XVII lactone of Chart A(Part II), for example, with lithium aluminum hydride or diisobutylaluminum hydride at a temperature ranging from 0° to 35° C. Forpreparing the formula XXVII compound, a Williamson synthesis is employedfollowed by hydrolysis of the blocking group. For example, the formulaXXVI compound is condensed with a haloalkanoate within the scope of

    Hal--(CH.sub.2).sub.g --CH.sub.2 --COOR.sub.1,

wherein Hal is chloro, bromo, or iodo and g is as defined above.Normally the reaction is done in the presence of a base such asn-butyllithium, phenyllithium, trimethyllithium, sodium hydride, orpotassium t-butoxide.

Alternatively and preferably, an ortho-4-bromoalkanoate is employed.Such reagents are available or are prepared by methods known in the art,for example, from the appropriate halonitrile by way of thecorresponding imino ester hydrohalide as illustrated hereinafter.

The condensation is conveniently run in a solvent, such astetrahydrofuran or dimethyl sulfoxide or especially if an organolithiumcompound is employed, preferably with addition of dimethylformamide orhexamethylphosphoramide. The reaction proceeds smoothly at -20° to 50°C., but is preferably performed at ambient temperature. Following thecondensation, the formula XXVII compound is obtained by methods known inthe art, for example, by hydrolysis in cold dilute mineral acid.

With regard to Chart A (Part IV), the formula XXIX compound is preparedfrom the formula XXVIII compound by a Wittig alkylation, using theappropriate (ω-carboxyalkyl)triphenylphosphonium bromide. The reactionproceeds as is generally known in the art, by first mixing theappropriate (ω-carboxyalkyl)triphenylphosphonium bromide with sodiodimethyl sulfinylcarbanide, at ambient temperature, and adding theformula XXVIII lactol to this mixture. Thereafter the carboxy hydrogenof the compound so formed is transformed to an R₁ moiety by the methodsand procedures hereinbelow described.

The formula XXX compound is prepared from the formula XXIX compound bycatalytic hydrogenation of the formula XXVIII compound. Methods known inthe art for transformation of PG₂ -type compounds to PG₁ -type compoundsare employed. Accordingly, metal catalysts (e.g. palladium) on asuitable support (e.g. carbon) at about 0° C. are employed under ahydrogen atmosphere. See for reference B. Samuelsson, Journal ofBiological Chemistry 239, 491 (1974). Accordingly there is prepared theformula XXX 11-deoxy-11α- or 11β-deoxy-TXB₁ -type compound.

Alternatively, and preferably the method of Chart A (Part VI) isemployed in the preparation of TXB₁ analogs as in formula XXX.

With regard to Chart A (Part V) the formula XXXII compound is preparedfrom the formula XXXI compound by optional reduction and a separation ofany mixed 15-epimers.

The mixed C-15 epimers are separated by conventional (e.g.chromatographic) means for separating diastereomeric mixtures. When15-methyl-TXB analogs are prepared (i.e. R₆ is hydrogen, R₅ is methyl)epimeric separation is deferred until after the deacetalization, sincethe deacetalization conditions result in C-15 epimerization in thiscase. Otherwise, C-15 epimers are optionally separated at any convenientpoint in the synthesis of Chart A.

Finally the reduction proceeds with reagents known to reduce carboxylicacids to corresponding primary alcohols. For example, when the formulaXXXII compound is an acid or an ester, the reduction proceeds withlithium aluminum hydride or diisobutylauminum hydride.

Useful solvents include diethyl ether, tetrahydrofuran, dimethoxyethane,or like organic solvents. The reaction is conveniently run attemperatures of about -78° C. to 100° C., although preferably at about0° C. to 50° C. When the formula XXXII compound is an acid, reducingagents such as diborane are also employed when double bond reduction isnot a problem.

Thereafter the formula XXXIII compound is prepared by optionaldialkylacetalizing the formula XXII compound, See methods described inU.S. Pat. No. 4,020,173 for the analogous transformation.

Chart A (Part VI) provides a method whereby the formula XXXIV compound(prepared as described in U.S. Pat. No. 4,020,173 is transformed into aformula XXXIX TXB₁ analog.

The formula XXXV compound is prepared from the formula XXXIV compound byreduction of the formula XXXIV lactone to a lactol, for example, asdescribed in Chart A (Part I) for the transformation of the formula XIVcompound to the formula XV compound.

Thereafter, the formula XXXV compound is Wittig carboxyalkylated asdescribed in Chart A (Part IV).

This formula XXXVI compound is then subjected to catalytichydrogenation, whereby the cis-5,6-unsaturation is removed and thearylmethyl hydroxy-hydrogen replacing group according to R₃₄ ishydrogenolyzed. Methods known in the art are employed. For example, seethe procedure and references cited in Chart A (Part IV) for thetransformation of the formula XXIX compound to the formula XXX compound.

Further, the formula XXXVIII compound is prepared from the formulaXXXVIII compound by oxidation of the formula XXXVII primary alcohol tothe corresponding aldehyde. For this purpose, Moffatt oxidationconditions are employed, as described in U.S. Pat. No. 4,020,173 for thetransformation of the formula LXIII compound of Chart C therein to theformula LXIV compound.

Thereafter, the formula XXXVIII compound is transformed to the formulaXXXIX TXB₁ analog by methods and procedures hereinabove described inChart A. For example, first the formula XXXVIII compound is subjected aWittig oxoalkylation as described in Chart A (Part I); thereafteroptionally hydrogenated (when Y₁ is --CH₂ CH₂ --); the oxo moietyreduced or methylated, thereby transforming it to an M₅ moiety; theresulting compound thereafter optionally dealkylacetalated; and finallyany mixed epimeric alcohols are separated by conventional means.

Chart D (Parts I and II) provide a methods whereby the formula LXIPGF.sub.α -type, 11,15-diacylate or bis(ether) or formula LXIX PGF.sub.α-type, 1,9-lactone, 15-acylate or ether is transformed to the variousformula LXVI or LXVII thromboxane analogs. The formula LXI compound ofChart D is known in the art or prepared by methods known in the art. Forexample, Chart B provides a method whereby various PGF.sub.α -typecompounds are transformed to corresponding PGF.sub.α -type9,15-diacylates. The formula LXIX is prepared, as described in Chart D(Part II) from the readily available formula LXVIII compound. See ChartB, formula XLIII. Chart B requires as starting material various formulaXL PGF.sub.α -type compounds which are known in the art or readilyprepared by methods known in the art. For example, when Z₁ of formula XLis the same as Z₄, then the various compounds so depicted are preparedby general methods described in Chart A employing as starting material abicyclic lactone aldehyde of the formula ##STR81## and modifying thereaction sequence of Chart A by methods such as those described in E. J.Corey, et al., JACS 92:397 (1970). Otherwise, the method of Chart Cprovides such compounds wherein Z₁ is ##STR82## from known startingmaterials.

Thus, with respect to Chart B one method is provided whereby the formulaXL PGF.sub.α -type compound is transformed to the PGF.sub.α, 15-acylateor 5-ether of formula XLIII or to the PGF.sub.α, 9,15-diacylate or9,15-bis(ether) formula L, which is required as starting material forthe process steps of Chart D.

In many cases, simpler more direct methods are available for thepreparation of such diacylates and bis(ethers) and are preferablyemployed in place of the method of Chart B. For example, when there isno steric hinderance about C-15, e.g., when R₃, R₄, and R₅ are allhydrogen, formula XL compound is transformed to an 11,15-bis-silyl etheraccording to the selective silylation procedure described in thetransformation of the formula XLIII compound to the formula XLVIIIcompound. This bis(silyl ether) is then acylated or etherified as in thetransformation of the formula XLI compound to the formula XLII compoundand the silyl group thereafter hydrolyzed, either by general methods orwhen R₁₀ blocking groups are introduced, by the selective proceduresdescribed above. Thereafter the procedure described in U.S. Pat. No.4,020,173 is employed for the 15-monoacylation or 15-mono etherificationof the resulting PGF.sub.α -type 9-acylate.

Alternatively, when, for example, R₅ is methyl the formula XL compoundis transformed to a corresponding 11-silyl ether by this selectivesilylation procedure referred to above. This 11-silyl ether is thenacylated or etherified at C-9 and C-15, as described above, and finallythe silyl group is hydrolyzed, under selective conditions as required,as described above, yielding the desired diacylate or bis(ether).

In any event, however, the process of Chart B invariably provides, inhigh yield, the required 9,15-diacylate, or 9,15-bis(ether) regardlessof the steric hindrance or lack thereof, of the formula XL startingmaterial.

The formula XLI compound is prepared from the formula XL compound bycycloalkyl or aryl boronization. Accordingly, the formula XLI compoundis prepared by reaction of the formula XL compound with a slightstoichiometric excess of the corresponding alkyl or aryl boronic acid.The course of the reaction is conveniently monitored by gaschromatography and the reaction is preferably carried forth on vigorousstirring at reflux temperatures. The preferred reaction diluent for thetransformatin is methylene chloride, although other suitable organicsolvents are likewise employed.

The formula XLII compound is then prepared from the formula XLI compoundby introduction of a hydroxy-hydrogen replacing group according to R₃₁at C-15. Methods and procedures described in U.S. Pat. No. 4,020,173 areemployed. The choice of the replacing group herein is made in accordwith considerations of convenience and ready availability of reactants,and thus, for example, acetyl groups provide conveniently employablemoieties. Further, arylmethyl groups must be avoided where unsaturatedthromboxane analogs are to be prepared in Chart D.

The formula XLIII compound is then prepared from the formula XLIIcompound by decycloboronization. For this purpose an alkaline metalhydroxide (e.g. sodium, lithium, or potassium hydroxide) is combinedwith the formula XLII compound in a water miscible diluent capable ofyielding a homogeneous reaction mixture (e.g. methanol or ethanol), andthe resulting solution is thereafter treated with dilute aqueoushydrogen peroxide. However, when acyl protecting groups according to R₉are employed in the preceding reaction, the decycloboronizationconditions must be adjusted to avoid deacylation. Thus alkanoic hydrogenperoxide in the presence of no more than a trace of hydroxide isemployed at about 30° C.

The formula XLIII compound is then selectively monosilylated at C-11,thereby preparing the formula XLVIII compound. For this selectivemonosilylation procedures described in U.S. Pat. No. 3,822,303 issuedJuly 2, 1974; German Offenlegungsschrift Pat. No. 2,259,195 (DerwentFarmdoc CPI No. 36457U-B) or Netherlands Pat. No. 7,214,142 (DerwentFarmdoc CPI No. 2622U-B) are employed. Silyl groups, are selected fromthose described hereinabove according to the criteria set forth whenselective silylations are to be employed.

The formula XLIX compound is then prepared from the formula XLVIIIcompound by acylation or etherification at C-9. Methods and proceduresdescribed above for the introduction of hydroxy-hydrogen replacinggroups according to R₃₁ are employed. Finally, the formula L PGF.sub.α-type 9,15-diacylate or 9,15-bis(ether) is prepared from the formulaXLIX compound by hydrolysis of the silyl group at C-11. Methods known inthe art and described above for the hydrolysis of silyl groups (mildacidic conditions or selective hydrolytic conditions) are employed.

As discussed above, Chart C provides a method whereby the formula LI3,7-inter-m-phenylene- or 3,7-inter-m-phenylene-3-oxa-PGF.sub.α-typecompound is transformed to a like formula LVII with various terminalside chains. The compounds according to formula LI which are employed asstarting material for Chart C are known in the art or readily availableby methods known in the art. For example, see U.S. Pat. No. 3,933,900,particularly Chart L therein which describes the preparation of3,7-inter-m-phenylene-3-oxa-PGF₂α.

With respect to Chart C, the formula LII compound is prepared from theformula LI compound by cleavage of the 13,14-trans double bond,conveniently by ozonolysis. Ozonolysis proceeds by bubbling dry oxygen,containing about 3 percent ozone, through a mixture of a formula LIcompound in a suitable nonreactive diluent. For example, n-hexane isadvantageously employed. The ozone may be generated using methods knownin the art. See, for example, Fieser, et al., "Reagents for OganicSynthesis," John Wiley and Sons, Inc. (1967), pages 773-777. Reactionconditions are maintained until the reaction is shown to be complete,for example, by silica gel thin layer chromatography or when thereaction mixture no longer rapidly decolorizes a dilute solution ofbromine in acetic acid.

The formula LIII compound is prepared from the formula LII compound byacylation, employing methods described above for introducing acylprotecting groups according to R₉.

The formula LIV compound is then prepared from the formula LIII compoundemploying a phosphonate of the formula: ##STR83## wherein R₁₅, L₁, andR₇ are as defined above. Phosphonates of this general formula areprepared by methods known in the art. See the text hereinaboveaccompanying Chart A for discussion of the preparation and theappropriate reaction conditions by which the Wittig reaction proceeds.The formula LV compound is prepared from the formula LIV compound bytransformation of the C-13 to C-14 trans--CH═CH--moiety to a Y₁ moiety.Methods discussed in Chart A above are employed.

The formula LV compound is then transformed to the corresponding formulaLVI compound by transformation of the 15-keto to an M₅ moiety, employingmethods described above in Chart A.

Finally the formula LVI compound prepared above is transformed to theformula LVII compound by deacylation, employing methods described abovefor removal of acyl protecting groups according to R₉, followed by achromatographic separation of C-15 epimeric mixtures.

Chart D provides a method whereby the various TXB₂ analogs herein areprepared from the formula LXI compound compound. Chart D provides apreferred method for preparing compounds wherein Y₁ is trans--CH═CH--.For those formula XLV or XLVI compounds wherein Z₁ contains no doublebonds, and Y₁ is --CH₂ CH₂ --, a modified method according to Chart D isemployed as the preferred method for preparing such compounds, whichcomprises employing an unsaturated formula LXI or LXIX starting material(i.e., Y₁ is trans-CH═CH--) transforming this material to thecorresponding formula LXIV or LXXII compound, catalyticallyhydrogenating this formula LXIV or LXXII compound, and finallyproceeding to the desired product as in Chart D (Part I).

With regard to Chart D (Part I), the formula LXI compound is transformedto the formula LXII aldehyde by reaction with lead tetraacetate inbenzene. The reaction proceeds rapidly at temperatures of about 40° to60° C., and is ordinarily complete within about 45 min. to 2 hr. Theresulting formula LXII product exhibits limited stability and isaccordingly converted to the formula LXIII acetal without furtherpurification.

The preparation of the formula LXIII dialkyl acetal proceeds by methodsknown in the art for the preparation of acetals from aldehydes, e.g.reaction with an alkanol in the presence of a triallyl, orthoalkanoateand catalytic amount of an acid. See U.S. Pat. No. 4,020,173. Thus, whenR₃₃ is methyl, the present reaction proceeds by treatment of the formulaLXII compound with methanol, methylorthoformate, and pyridinehydrochloride. Pure formula LXIII product is thereafter isolated byconventional methods, such as chromatography.

The formula LXIV compound is then prepared from the formula LXIIIcompound by removal of the diacyl of bis-(ether) groups. Methodsdescribed hereinabove are employed. For example, when R₃₁ is acyl,sodium methoxide in methanol is employed in stoichiometric amounts,yielding the formula LXIV trihydroxy acetal. Optionally, the use ofaqueous methanolic sodium hydroxide removes both such acyl protectinggroups and the R₁ ester.

The formula LXV compound is then prepared from the formula LXIV compoundby hydrolysis of the acetal group. Methods described above for thehydrolysis of tetrahydropyranyl ethers (i.e. acetic acid, water, andtetrahydrofuran mixtures) yield the formula LXV product. More vigorousconditions of hydrolysis of the formula LXIV compound yield the formulaLXVI product wherein R₆ is hydrogen directly.

Optionally, however, the formula LXV compound is prepared directly formthe formula LXII compound when R₃₁ is an acyl protecting group accordingto R₉ by treatment of such a formula LXII compound with an alkanol andanhydrous mineral acid in diethyl ether. When R₃₃ is methyl, forexample, methanol and ethereal 2N hydrochloric acid yield the formulaLXV compound directly form such a formula LXII reactant.

Finally, the formula LXVI and LXVII compounds are prepared as describedin Chart A for the preparation of the formula XXXII and formula XXXIIIcompounds, respectively, from the formula XXXI reactant.

With respect to Chart D (Part II) an alternate method is provided forthe preparation of the formula LXXII compound, which compound beingidentical to the formula LXIV compound of Chart D (Part I), is useful inthe synthesis of various compounds of the present invention. The formulaLXIX compound of Chart D is successively transformed to the formula LXX,formula LXXI, and formula LXXII compounds as in the correspondingtransformations of Chart D (Part I) wherein the formula LXI compound issuccessively transformed to the formula LXII, formula LXIII, and formulaLXIV compound respectively.

The formula LXIX compound is prepared from the formula LXVIII reactant(available as the formula XLIII compound of Chart B, according toprocess of that Chart) by a 1,9-lactonization. This 1,9-lactonizationproceeds by methods known in the art. For a discussion of a generalmethod for preparing large ringed lactones, see E. J. Corey, Journal ofthe Americal Chemical Society 96, 5614 (1974); and for a discussion ofthe 1,9-lactonization of PGF₂.sbsb.α see E. J. Corey, et al., Journal ofthe Americal Chemical Society 97, 653 (1975). Thus, by thislactonization procedure the formula LXVII free acid is transformed to a2-pyridine thiol ester by reaction of the formula LXVIII free acid with1.5 equivalents of 2,2'-dipyridyldisulfide and 1.5 equivalents oftriphenylphosphine in dry (anhydrous) oxygen-free xylene or benzene. The2-pyridinethiol esterification proceeds at room temperature, in about 2to 24 hr. Therafter ring closure is accomplished by first diluting thethiol ester with dry oxygen-free xylene or benzene and thereafterheating at reflux for 1 to 24 hr.

In the reaction sequence described by Charts B and D, the use of C-1esters, particularly and especially lower alkyl esters, is preferred.

In each of the above Charts, diastereomeric mixtures, other thananomeric mixtures, when produced by any reaction step herein, areseparated immediately by isolation and conventional separationtechniques, e.g., chromatography.

Optically active TXB analogs and related products are obtained fromoptically active intermediates, according to the process steps of theabove charts. Likewise racemic TXB₂ analogs are obtained fromcorresponding racemic TXB₂ intermediates following the procedures in theabove charts, e.g. when racemic intermediates are used in the reactionsabove, racemic products are obtained.

In all of the above described reactions, the products are separated byconventional means from starting material and impurities. For example,by use of silica gel chromatography monitored by thin layerchromatography the products of the various steps of the above charts areseparated from the corresponding starting materials and impurities.

As discussed above, the processes herein described lead variously toprimary alcohols acids (R₁ is hydrogen) or to esters.

When the alkyl ester has been obtained and an acid is desired,saponification procedures, as known in the art for PGF-type esters areemployed. Optionally, however, free acids are prepared by enzymaticprocess for transformation of PGE-type esters to their acid forms. Thusthe TXB-type, methyl ester is combined with prepared enzyme powder andhydrolyzed. See for reference E. G. Daniels, Process For Producing AnEsterase, U.S. Pat. No. 3,761,356.

When an acid has been prepared and an alkyl, cycloalkyl, or aralkylester is desired, esterification is advantageously accomplished byinteraction of the acid with the appropriate diazohydrocarbon. Forexample, when diazomethane is used, the methyl esters are produced.Similar use of diazoethane, diazobutane, and 1-diazo-2-ethylhexane, anddiazodecane, for example, gives the ethyl, butyl, and 2-ethylhexyl anddecyl esters, respectively. Similarly, diazocyclohexane andphenyldiazomethane yield cyclohexyl and benzyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is completethe solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbns are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, John Wiley andSons, Inc., New York, N.Y. vol. 8, pp. 389-394 (1954).

An alternative method for alkyl, cycloalkyl or aralkyl esterification ofthe carboxy moiety of the acid compounds comprises transformation of thefree acid to the corresponding silver salt, followed by interaction ofthat salt with an alkyl iodide. Examples of suitable iodides are methyliodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide,cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide,and the like. The silver salts are prepared by conventional methods, forexample, by dissolving the acid in cold dilute aqueous ammonia,evaporating the excess ammonia at reduced pressure, and then adding thestoichiometric amount of silver nitrate.

Various methods are available for preparing phenyl or substituted phenylesters within the scope of the invention from corresponding aromaticalcohols and the free acid TXB-type compounds, differing as to yield andpurity of product.

Thus by one method, the TXB-type compound is converted to a tertiaryamine salt, reacted with pivaloyl halide to give the mixed acidanhydride and then reacted with the aromatic alcohol. Alternatively,instead of pivaloyl halide, an alkyl or arylsulfonyl halide is used,such as p-toluenesulfonyl chloride. See for example Belgian Pat. Nos.775,106 and 776,294, Derwent Farmdoc Nos. 33705T and 39011T.

Still another method is by the use of the coupling reagent,dicyclohexylcarbodiimide. See Fieser et al., "Reagents for OrganicSynthesis", pp. 231-236, John Wiley and Sons, Inc., New York, (1967).The TXB-type compound is contacted with one to ten molar equivalents ofthe aromatic alcohol in the presence of 2-10 molar equivalents ofdicyclohexylcarbodiimide in pyridine as a solvent.

One preferred novel process for the preparation of these esters,however, comprises the steps:

a. forming a mixed anhydride with the TXB-type compound andisobutylchloroformate in the presence of a tertiary amine and

b. reacting the anhydride with an appropriate aromatic alcohol.

The mixed anhydride described above is formed readily at temperatures inthe range -40° to +60° C., preferably at -10° to +10° C. so that therate is reasonably fast and yet side reactions are minimized. Theisobutylchloroformate reagent is preferably used in excess, for example1.2 molar equivalents up to 4.0 per mole of the TXB-type compound. Thereaction is preferably done in a solvent and for this purpose acetone ispreferred, although other relatively nonpolar solvents are used such asacetonitrile, dichloromethane, and chloroform. The reaction is run inthe presence of a tertiary amine, for example triethylamine, and theco-formed amine hydrochloride usually crystallizes out, but need not beremoved for the next step.

The aromatic alcohol is preferably used in equivalent amounts or insubstantial stoichiometric excess to insure that all of the mixedanhydride is converted to ester. Excess aromatic alcohol is separatedfrom the product by methods described herein or known in the art, forexample by crystallization. The tertiary amine is not only a basiccatalyst for the esterification but also a convenient solvent. Otherexamples of tertiary amines useful for this purpose includeN-methylmorpholine, triethylamine, diisopropylethylamine, anddimethylaniline. Although they are effectively used, 2-methylpyridineand quinoline result in a slow reaction. A highly hindered amine such as2,6-dimethyllutidine is, for example, not useful because of the slownessof the reaction.

The reaction with the anhydride proceeds smoothly at room temperature(about 20° to 30° C.) and can be followed in the conventional mannerwith thin layer chromatography (TLC).

The reaction mixture is worked up to yield the ester following methodsknown in the art, and the product is purified, for example by silica gelchromatography.

Solid esters are converted to a free-flowing crystalline form oncrystallization from a variety of solvents, including ethyl acetate,tetrahydrofuran, methanol, and acetone, by cooling or evaporating asaturated solution of the ester in the solvent or by adding a misciblenonsolvent such as diethyl ether, hexane, or water. The crystals arethen collected by conventional techniques, e.g. filtration orcentrifugation, washed with a small amount of solvent, and dried underreduced pressure. They may also be dried in a current of warm nitrogenor argon, or by warming to about 75° C. Although the crystals arenormally pure enough for many applications, they may be recrystallizedby the same general techniques to achieve improved purity after eachrecrystallization.

The compounds of this invention prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed hereinbove. These transformations arecarried out by a variety of procedures known in the art to be generallyuseful for the preparation of inorganic, i.e., metal or ammonium salts.The choice of procedure depends in part upon the solubilitycharacteristics of the particular salt to be prepared. In the case ofthe inorganic salts, it is usually suitable to dissolve an acid of thisinvention in water containing the stoichiometric amount of a hydroxide,carbonate, or bicarbonate corresponding to the inorganic salt desired.For example, such use of sodium hydroxide, sodium carbonate, or sodiumbicarbonate gives a solution of the sodium salt. Evaporation of thewater or addition of a water-miscible solvent of moderate polarity, forexample, a lower alkanol or a lower alkanone, gives the solid inorganicsalt if that form is desired.

To produce an amine salt, an acid of this invention is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingan acid of this invention with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water solution, followedby evaporation of the water.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples andpreparations.

All temperatures are in degrees centigrade.

IR (infrared) absorption spectra are recorded on a Perkin-Elmer Model421 or 137 infrared spectrophotometer. Except when specified otherwise,undiluted (neat) samples are used.

UV (Ultraviolet) spectra are recorded on a Cary Model 15spectrophotometer.

NMR (Nuclear Magnetic Resonance) spectra are recorded on a Varian A-60,A-60D, or T-60 spectrophotometer in deuterochloroform solutions withtetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on an CEC model 21-11OB Double Focusing HighResolution Mass Spectrometer on an LKB Model 9000 Gas-Chromatograph-MassSpectrometer. Trimethylsilyl derivatives are used, except whereotherwise indicated.

"Brine" herein, refers to an aqueous saturated sodium chloride solution.

The A-IX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid-cyclohexane-water (90:20:50:100) asmodified from M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257(1966).

Skellysolve-B (SSB) refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC (thin layer chromatography) to contain the pure product(i.e., free of starting material and impurities).

Melting points (MP) are determined on a Fisher-Johns or Thomas-Hoovermelting point apparatus.

EXAMPLE 1 2,2-Difluoro-TXB₂ (Formula XXXII M₁ is ##STR84## Z₄ iscis--CH═CH--(CH₂)₂ --CF₂ --, Y₁ is trans--CH═CH--, R₁, R₃, R₄, and R₆are hydrogen, and R₇ is n-butyl) its methyl ester, the 11α-methylacetals thereof or the 15-epimers thereof.

Refer to Chart A (Parts I, IV, and V).

A. 2β-Carboxaldehyde-4α-hydroxy-6α-methoxy-3α-tetrahydropyranacetic acidγ-lactone as prepared in U.S. Pat. No. 4,020,173, Example 14, part A(425 mg.) is dissolved in 20 ml. of diethyl ether and the solutiontreated with 4.8 ml. of 0.5 M 2-oxo-heptylidine-tri-n-butyl phosphoranein diethyl ether. After 20 min., the reaction mixture is evaporated andthe residue chromatographed on 80 g. of silica gel. The column is elutedwith ethyl acetate in n-hexane (1:1) and fractions containing pure3α-hydroxy-5α-methoxy-2β-(3-oxo-trans-1-octenyl)-3α-tetrahydropyranaceticacid γ-lactone, a formula XII compound, are combined (524 mg.) NMRabsorptions are observed at 0.6-1.9, 1.9-3.0, 3.33, 4.25, 4.5-5.0, 6.4,and 6.80 δ. Infrared absorptions are observed at 2900, 1780, 1670, 1160,1130, 1070, 1050, and 1025 cm.⁻¹. The mass spectrum exhibits parent peakat 296.1589. Silica gel TLC R_(f) is 0.43 in ethyl acetate andSkellysolve B (1:1).

B. To a mixture of 2.18 g. of anhydrous zinc chloride and 15 ml. of1,2-dimethoxyethane under a nitrogen atmosphere is added with stirring0.61 g. of sodium borohydride. The resulting mixture is then stirred atambient temperature for 2 hr. and thereafter cooled to -15° C. Asolution of 1.17 g. of the reaction product of Part A in 10 ml. of1,2-dimethoxyethane is then added dropwise over about 2 min. The mixtureis then stirred at -15° C. for 2 hr., thereafter at 0° C. for one hr.and finally at ambient temperature for about 1.5 hr. The mixture is thencooled to 0° C. and 4.4 ml. of water is added dropwise, with caution(hydrogen gas evolution). The resulting mixture is then diluted with 75ml. of ethyl acetate and filtered through Celite. The filtrate is thenwashed with 30 ml. of brine and the organic layer dried over magnesiumsulfate and concentrated under reduced pressure. The resulting residue(1.24 g.) is then chromatographed on 125 g. of silica gel, deactivatedby addition of 25 ml. of ethyl acetate. Eluting with 500 ml. of ethylacetate and hexane (3:1) and 500 ml. of ethyl acetate affords 1.05 g. of4α-hydroxy-6α-methoxy-2β-[(3RS)-3-hydroxy-trans-1- acidoctenyl]3α-tetrahydropyranacetic γ-lactone (formula XIV). Epimericalcohols are then separated employing silica gel thin layerchromatography, eluting with methanol and chloroform (1:19).Alternatively, the epimeric mixture of alcohols is employed directly insucceeding parts of the present example. For the epimeric mixture, acharacteristic NMR absorption is observed at 3.27 δ. The mass spectrumexhibits a parent peak at 370.2194 and other peaks at 369, 345, 329,327, 323, 229, 267, 247, 241, 199, 185, 173, and 129.

C. To a stirred solution of 1.05 g. of the epimeric mixture of thereaction production of part C in 15 ml. of toluene and 10 ml. of drytetrahydrofuran at -78° C. under a nitrogen atmosphere is added 15 ml.of a 10 percent solution of diisobutylaluminum hydride in toluene over a5 min. period. The mixture is stirred for 20 min. and thereafter asolution of 3 ml. of water and 10 ml. of tetrahydrofuran is addedcautiously with vigorous stirring. The resulting mixture is allowed towarm to ambient temperature and then filtered through Celite, rinsingwith ethyl acetate. The filtrate is then shaken with 30 ml. of brine andthe resulting mixture filtered through Celite. The filtrate is thenwashed with brine, and concentrated under reduced pressure to yield 1.0g. of a formula XV compound;4α-hydroxy-6α-methoxy-2β-[(3RS)-3-hydroxy-trans-1-octenyl]-3α-tetrahydropyranacetic acid γ-lactol, an oil. Silica gel TLC R_(f) is 0.21 and 0.24 inmethanol and chloroform (1:19).

Alternatively reaction product of part C is prepared directly from thereaction product of part A as follows:

The reaction product of part A (500 mg.) is dissolved in 10 ml. oftetrahydrofuran and the solution cooled to -78° C. under an argonatmosphere. This stirred solution is then treated over 30 min. with 0.7ml. of diisobutylaluminum hydride, diluted to 2.8 ml. with toluene. Thereaction mixture is then treated dropwise with 2 ml. of water andallowed to warm to ambient temperature. Ethyl acetate in 0.25 N aqueoushydrochloric acid are added to the reaction mixture, and the mixturepartitioned between organic and aqueous phases. The organic phase iswashed with brine, dried over magnesium sulfate and concentrated underreduced pressure to yield 0.364 g. of a crude oil, the (3RS)-3-hydroxyformula XXV compound, as above.

D. A mixture of 1.69 g. of 57 percent sodium hydride in mineral oil and45 ml. of dry dimethylsulfoxide are stirred slowly under nitrogen at65°-70° C. for one hr. This solution is then cooled to 15° C. and 9.0 g.of 4,4-difluoro-4-carboxybutyltriphenphosphonium bromide is added. Theresulting orange mixture is then stirred for 30 min. at ambienttemperature, cooled to 15° C. and the solution of 1.0 g. of the reactionproduct of part C in 5 ml. of dimethyl sulfoxide is added. The resultingmixture is then stirred at ambient temperature for 2.5 hr. and is thencooled to 15° C. Water is added with cooling, yielding a solution ofabout pH 9. This solution is then extracted with diethyl ether to removeneutral materials. To the aqueous layer is added a suspension of 10 g.of ammonium chloride in 60 ml. of brine and the resulting mixtureextracted with ethyl acetate. The ethyl acetate extract is then washedwith brine, dried over magnesium sulfate, and concentrated under reducedpressure. The resulting residue (1.5 g.) is is chromatographed on 100 g.of acid-washed silica gel, deactivated by addition of 20 ml. of ethylacetate. Eluting with one l. of ethyl acetate and hexane (1:1) yields11-deoxy-11α-methoxy-15-epi-2,2-difluoro-TXB₂, and11-deoxy-11α-methoxy-2,2-difluoro-TXB₂.

E. Methyl esterification employing ethereal diazomethane, yields2,2-difluoro-11-deoxy-11α-methoxy-TXB₂, methyl ester, or its 15-epimer.

F. A solution of one ml. of 85 percent aqueous phosphoric acid and 10ml. of water is added with stirring to a solution of 220 mg. of thereaction product of part D the (15S)- or (15R)-epimer in 10 ml. oftetrahydrofuran. The resulting solution is then heated to 40° C. for 6hr. and sodium chloride is thereafter added to the mixture. Theresulting mixture is extracted with ethyl acetate and the ethyl acetateextract washed with brine until the aqueous layer is neutral. Theorganic phase is then dried over magnesium sulfate and concentrated to aresidue. The residue (210 mg.) is then chromatographed on 20 g. ofacid-washed silica gel, deactivated by addition of 4 ml. of ethylacetate. Eluting with 70 ml. of ethyl acetate and hexane (3:1), and 100ml. of ethyl acetate yields the title 2,2-difluoro TXB₂ or its 15-epimerrespectively.

G. Methyl esterification, of the reaction product of part F, employingethereal diazomethane, yields 2,2-difluoro-TXB₂, methyl ester or its15-epimer.

EXAMPLE 2 13,14-Dihydro-TXB₂ (Formula XXXII: R₁, R₅ of the M₁ moiety, R₃and R₄ of the L₁ moiety, and R₆ are all hydrogen, Z₄ iscis--CH═CH--(CH₂)₃ --, Y₁ is --CH₂ CH₂ --, and R₇ n-butyl) its11α-methylacetal, the methyl esters thereof, or the 15-epimers thereof.

Refer to Chart A. (parts I, IV, and V).

A. A mixture of 4 g. of the reaction product of Example 1, part A, 800mg. of a 5 percent palladium-on-charcoal catalyst, and 400 ml. of ethylacetate are stirred at ambient temperature under one atmosphere ofhydrogen for one hr. Hydrogen uptake proceeds rapidly, and the reactionis terminated when silica gel TLC indicates the reaction is complete.The resulting mixture is then filtered through Celite and washed withethyl acetate. The filtrate is then evaporated to yield a formula XIIIcompound:3α-hydroxy-5α-methoxy-2β-(3-oxo-octyl)-3α-tetrahydropyranacetic acidγ-lactone.

B. Following the procedure of Example 1, parts B and C, the reactionproduct of Example 1, part A, is transformed to4α-hydroxy-6α-methoxy-2β-[(3RS)-3-hydroxyoctyl]-3α-tetrahydropyranaceticacid γ-lactol, a formula XV compound.

C. Following the procedure of Example 1, part D, but employing4-carboxybutyltriphenylphosphonium bromide in place of4,4-difluoro-4-carboxybutyltriphenylphosphonium bromide there isprepared 11-deoxy-11α-methoxy-15-epi-13,14-dihydro-TXB₂ or11-deoxy-11α-methoxy-13,14-dihydro-TXB₂.

D. Following the procedure of Example 1, part E, F, and G, there areprepared the various title products of this example:11-deoxy-11α-methoxy-13,14-dihydro-TXB₂, methyl ester or its 15-epimer;13,14-dihydro-TXB₂, or its 15-epimer; and 13,14-dihydro-TXB₂, methylester or its 15-epimer.

EXAMPLE 3

15-Methyl-TXB₂ (Formula XXXII: R₁, R₆ and R₃ and R₄ of the L₁ moiety areall hydrogen, R₅ of the M₁ moiety is methyl, Z₄ iscis---CH═CH--(CH₂)_(g) --, Y₁ is trans--CH═CH--, and R₇ is n-butyl) its15 -epimer, the 11α-methylacetals thereof, or the methyl esters thereof.

Refer to Chart A (Parts I, IV, and V).

A. The reaction product of Example 1, part A, in tetrahydrofuran istreated with stirring at -78° C. with 3M methyl magnesium bromide indiethyl ether, added dropwise. After 2 hr., there is added dropwise at-78° C. 10 ml. of saturated aqueous ammonium chloride. The resultingmixture is then warmed to 25° C. and shaken with diethyl ether andwater. The organic phase is then washed with brine and dried andconcentrated to yield4α-hydroxy-6α-methoxy-2β-[(3RS)-3-methyl-3-hydroxy-trans-1-octenyl]-3α-tetrahydropyranaceticacid γ-lactone, a formula XIV compound.

B. Following the procedure of Example 1, parts B and C, the procedure ofExample 2, part C and the procedure of Example 1, parts E, F, and G,successively, there are prepared the various title products:11-deoxy-11α-methoxy-15-methyl-TXB₂, or its 15-epimer;11-deoxy-11α-methoxy-15-methyl-TXB₂, methyl ester, or its 15-epimer;15-methyl-TXB₂, or its 15-epimer; and 15-methyl-TXB₂, methyl ester, orits 15-epimer.

EXAMPLE 4

TXB₁ (Formula XXXII: R₁, R₃ and R₄ of the L₁ moiety, R₅ and R₆ are allhydrogen, Z₄ is --(CH₂)₅ ---, Y₁ is trans--CH═CH--, and R₇ is n-butyl)its 15-epimer, the 11α-methylacetals thereof, and the methyl estersthereof.

Refer to Chart A (Parts, I, IV and V).

A. A mixture of TXB₂, its 15-epimer, the 11α-methylacetals thereof, orthe methyl esters thereof; a 5 percent rhodium-on-alumina catalyst; andethyl acetate is stirred under one atmosphere of hydrogen at 0° C. untilsubstantially all the starting material has been consumed as indicatedby silica gel TLC. The resulting mixture is then filtered to removecatalyst and the filtrate is concentrated under reduced pressure. Theresidue so obtained is then chromatographed on silica gel and fractionscontaining one of the respective pure title products are combined andconcentrated to yield the title compound.

EXAMPLE 5

cis-4,5-Didehydro-TXB₁ (Formula XXXII: R₁, R₃ and R₄ of the L₁ moiety,R₅ of the M₁ moiety and R₆ are all hydrogen, Z₄ is cis--CH₂--CH═CH--(CH₂)₂ --, Y₁ is trans--CH═CH-- , and R₇ is n-butyl) its15-epimer, the 11α-methylacetals thereof, or

Refer to Chart A (parts I, II, and V).

A. A mixture of the reaction product of Example 1, part B, (35.9 g.), 15ml. of freshly distilled dihydropyran, and 0.3 g. of pyridinehydrochloride in 100 ml. of dichloromethane is stirred under a nitrogenatmosphere at about 25° C. for 18 hr. The resulting mixture is thendiluted with cold diethyl ether and washed with ice-cold 0.1 Nhydrochloric acid, water, 5 percent aqueous sodium bicarbonate, andbrine. This solution is then dried and concentrated under reducedpressure and chromatographed yielding the THP ether of the startingmaterial:6α-methoxy-4α-hydroxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-tetrahydropyranaceticacid γ-lactone, a formula XVII compound.

B. The reaction product of part A above is transformed to6α-methoxy-4α-hydroxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-tetrahydropyranaceticacid γ-lactol following the procedure of Example 1, part C.

C. Methyltriphenylphosphonium bromide (17.5 g.) is added to a solutionof sodiodimethylsulfinylcarbanide prepared from sodium hydride (57percent, 2.02 g.) and 75 ml. of dimethylsulfoxide at 65° to 70° C.) andcooled to 15° C. The resulting mixture is then stirred at 15° to 25° C.for 20 min., and cooled to 15° C. To this solution is added a mixture ofthe reaction product of part B above (10 g.) in 20 ml. ofdimethylsulfoxide. The resulting mixture is then stirred at about 25° C.for 2.5 hr., and then shaken with water and 500 ml. of diethyl ether.The organic phase is then washed with water and brine, dried, andconcentrated under reduced pressure. The residue is triturated withdiethyl ether and then Skellysolve B and filtered and the filtrateevaporated to yield a residue which is chromatographed on silica gelyielding 6α-methoxy-4α-hydroxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-(2'-propenyl)-tetrahyropyran, a formula XIX compound.

D. To a solution of 5.2 g. of the reaction product of part C above in 50ml. of dry tetrahydrofuran at 0° C. under a nitrogen atmosphere is addedwith stirring 10 ml. of disiamylborane (bis(1,2-dimethylpropyl)borane),1M. in tetrahydrofuran. After 1 hr. at 0° C. there is added one ml. ofwater and (cautiously) a solution of one ml. of 50 percent aqueoussodium hydroxide in 20 ml. of methanol. To this mixture is added 15 ml.of 15 percent hydrogen peroxide, maintaining the reaction temperaturebelow 40° C. After stirring for one hr at about 25° C. the mixture isshaken with brine and ethyl acetate. The organic phase is then washedwith brine, dried and concentrated. The residue is then taken up inxylene and then concentrated again under reduced pressure. The productis then chromatographed on silica gel yielding a formula XX product:6α-methoxy-4α-hydroxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-(3-hydroxypropyl)-tetrahydropyran.

E. To a solution of 21.3 g. of the reaction product of part D above, 190ml. of tetrahydrofuran, and 100 ml. of hexamethyldisilizane at ambienttemperature is added with stirring 25 ml. of trimethylsilyl chloride.The resulting mixture is then allowed to stand at ambient temperatureuntil silica gel TLC indicates the formation of the bis-(trimethylsilyl)derivative is complete. Thereupon crude product is concentrated underreduced pressure and the residue diluted with 250 ml. of dry benzene.This benzene containing mixture is then filtered, the solids washed withbenzene, and the filtrate and washings combined and concentrated underreduced pressure to yield a formula XXI compound:6α-methoxy-4α-trimethylsilyloxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-(3-trimethylsilyloxypropyl)-tetrahydropyran.

F. To a solution of 100 ml. of dry methylene chloride in 6.2 ml. ofpyridine at 15° C. is added with stirring 3.09 g. of dried chromiumtrioxide. This mixture is then stirred at 20°-23° C. for 30 min. andthereafter cooled to 15° C. To this cooled mixture is then added asolution of 2.3 g. of the reaction product of part E above in 15 ml. ofmethylene chloride. The resulting mixture is then stirred at ambienttemperature for 30 min. Benzene (25 ml. and 3 g. of diatomaceous earth(Celite) are added to the mixture. The resulting mixture is thenfiltered through a bed of diatomaceous earth (Celite) and acid washedsilica gel. The resulting solids are then washed with ethyl acetate andthe filtrate and washings combined and concentrated under reducedpressure at ambient temperature to a residue which is mixed with ethylacetate and filtered by the method described above. This second filtrateand ethyl acetate washings are then combined and concentrated underreduced pressure at about 25° C., preparing the formula XXXII compound:6α-methoxy-4α-trimethylsilyloxy-2β-[(3RS)-3-tetrahydropyranyloxy-trans-1-octenyl]-3α-(3-oxopropyl)tetrahydropyran.

G. The reaction product of part F is reacted with a mixture oftetrahydrofuran, and acetic acid (1:3:6) at 40° C. for 4 hours.Thereafter the resulting mixture is diluted with water, freeze-dried,extracted with ethyl acetate, washed, dried, and concentrated to yieldthe formula XXIII lactol.

H. Following the procedure of Example 1, part D, but employing3-carboxypropyltriphenylphosphonium bromide in place of4,4-difluoro-4-carboxybutyltriphenylphosphonium bromide the reactionproduct of part G is transformed to a formula XXIV compound.Purification and separation of mixed C-15 epimers on silica gelchromatography yields 11-deoxy-11α-methoxy-cis-4,5-didehydro-TXB₁.

Following the procedure of Example 1, parts E, F, and G, there areprepared the various title products.

EXAMPLE 6 5-Oxa-TXB₁ (Formula XXXII: R₁, R₃ and R₄ of the L₁ moiety, M₅,and R₆ are all hydrogen, Z₄ is CH₂ --O--(CH₂)₃ --, Y₁ is trans--CH═CH--,and R₇ is n-butyl) its 15-epimer, the 11α-methyl acetals thereof, ormethyl esters thereof.

Refer to Chart A (parts I, III, and V).

A. A mixture of the reaction mixture of Example 5, part A (6.3 g.) and15 ml. of 95 percent ethanol is treated at 0° C., with stirring, with asolution of sodium borohydride (0.6 g.) in 10 ml. of water. Theborohydride is added over a period of about one min. The resultingmixture is then stirred at 0° C. for 10 min. and shaken with 20 ml. ofwater, 250 ml. of ethyl acetate, and 150 ml. of brine. The organic phaseis then washed with brine, dried, and concentrated under reducedpressure to yield a formula XXVI compound:5α-methoxy-4α-hydroxy-2β-[(3RS)-3-tetrahydropyanyloxy-trans-1-octenyl]-3α-(2-hydroxyethyl)-tetrahydropyran.

B. A solution of potassium t-butoxide (1.77 g.) in 30 ml. oftetrahydrofuran is mixed at 0° C., with stirring, with a solution of 5.8g. of the reaction product of part A above in 30 ml. of tetrahydrofuran.The resulting mixture is then stirred at 0° C. for 5 min. and thereafter5 ml. of trimethyl ortho-4-bromobutyrate (see U.S. Pat. No. 3,864,387)is added. Stirring is continued at 0° C. for 2 hr. and at about 25° C.for 16 hr. To this mixture is then added 30 ml. of dimethylformamide and0.5 g. of potassium-t-butoxide. The mixture is then stirred for 20 hr.Some of the solvent is then removed under reduced pressure and theresidue shaken with water and diethyl ether dichloromethane (3:1). Theorganic phase is then washed with water and brine, dried, andconcentrated. The residue containing the ortho ester is then dissolvedin 60 ml. of methanol at 0° C. and treated with 15 ml. of cold water,containing 2 drops of concentrated hydrochloric acid. The resultingmixture is then stirred at 0° C. for 5 min. and shaken with 200 ml. ofdiethyl ether, 50 ml. of dichloromethane, and 200 ml. of brine. Theorganic phase is then washed with brine, dried, and concentrated underreduced pressure. The residue is then subjected to silica gel,separating mixed 15-epimer and yielding 11-deoxy-11α-methoxy-5-oxa-TXB₁,methyl ester, 15-tetrahydropyranyl ether or its 15-epimer.

C. Following the procedure of Example 5, part G, the reaction product ofpart B is transformed to 11-deoxy-11α-methoxy-5-oxa-TXB₁, methyl esteror its 15-epimer.

D. The methyl esters of part B above are saponfied by reaction withdilute aqueous alcoholic sodium hydroxide. Thereafter, the sodium saltthusly prepared is acidified wit dilute aqueous hydrochloric acid,yielding 11-deoxy-11α-methoxy-5-oxa-TXB₁ or its 15-epimer.

E. Following the procedure of Example 1, parts F, and G, there areprepared 5-oxa-TXB₁ or its 15-epimer or 5-oxa-TXB₁, methyl ester or its15-epimer.

Following the procedures described in Example 1-6, and selecting theappropriate reactants and starting materials, there are prepared each ofthe various compounds described by formula XXXII.

Preparation 1

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF₁α(Formula LVII: R₁, R₃, and R₄ or the L₁ moiety, and R₅ of the M₁ moietyare all hydrogen, Z₃ is oxa, Y₁ is trans---CH═CH--, g is one, and R₇ isphenoxy).

Refer to Chart C.

A. 3,7-Inter-m-phenylene-4,5,6-trinor-PGF₁α, methyl ester (1 g.) in 200ml. of methanol is cooled to 0° C. in an ice bath. A stream of ozonegenerated from a conventional ozone producing apparatus is passedthrough the mixture until the starting material is completely consumed.Thereupon the resulting ozonide is treated with dimethylsulfide, withstirring and allowed to warm to ambient temperature. The resultingproduct is washed and concentrated and the residue chromatographedyielding the formula LII aldehyde. About 4.5 g. of the formula LIIaldehyde and 20 ml. of pyridine are subjected to dropwise addition of 4g. of benzoyl chloride. The resulting mixture is then stirred at 25° C.for about 24 hr. The reaction mixture is then cooled to 0° C. and 5 ml.of water is added with stirring over about 10 min. Thereafter theresulting mixture is extracted with diethyl ether and the ethereallayers are washed with sodium bisulfate, sodium bicarbonate, and brine;dried over magnesium sulfate; filtered; and concentrated under reducedpressure to yield the formula LIII dibenzoate.

B. Following the procedure of Example 1, part A, but employing dimethyl2-oxo-3-phenoxypropylphosphonate in place of dimethyl2-oxo-heptylphosphonate, there is prepared the formula LIV product.

C. Following the procedure of Example 1, part B, the reaction product ofpart B above is transformed to the formula LVI compound.

D. The reaction product of part C above in a solution of 2 percentbicarbonate in methanol stirred at -25° C. for 24 hr. and the resultingmixture acidified to pH 4 or 5 with sodium bisulfate and concentrated toa residue. The residue is then extracted with ethyl acetate and theethyl acetate extracts are washed with brine and dried over anhydrousmagnesium sulfate. The resulting mixture is then concentrated undervacuum and the residue chromatographed on silica gel TLC to yield puretitle free acid.

Preparation 2

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-PGF₁α,9,15-diacetate (formula L: R₁ and R₃ and R₄ of the L₁ moiety arehydrogen, Z₁ is ##STR85## R₃₁ is benzoyl, Y₁ is trans--CH═CH--, R₅ ofthe M₃ moiety is methyl, R₇ is phenoxy and R₃₁ of the M₃ moiety isbenzoyl).

Refer to Chart B.

A. A solution of the reaction product of Preparation 1 (800 mg.) and1-butaneboronic acid (250 mg.) in 25ml. of methylene chloride is heatedat reflux. After 15 min. the methylene chloride is allowed to distilloff slowly and fresh methylene chloride is added each time the totalvolume is reduced to about one-half of the original volume. After 90min. all of the methylene chloride is removed under reduced pressureyielding the formula XLI cyclic boronate of the starting material.

B. To the solution of about 0.8 g. of the reaction product of part Aabove in pyridine (5 ml.) is added acetic anhydride (2 ml.). The mixtureis then stirred for about 4 hr. under a nitrogen atmosphere andthereafter water (50 ml.) is added and the resulting mixture stirred foran additional one hr. The second resulting mixture is then extractedwith ethyl acetate and combined organic extracts are then washed, dried,and concentrated to yield the formula XLII 15-acetate.

C. The reaction product of part B above is dissolved in methanol inwater (2:1) and a 30 percent methanolic solution of hydrogen peroxide(about 4 equivalents per equivalent of cyclic boronate) is added. Thereaction mixture is maintained at ambient temperature, with stirring,until silica gel TLC indicates complete hydrolysis of the boronateester.

D. A solution of 0.60 g. of the reaction product of part C above in 70ml. of dry acetone is cooled to -20° C. Thereafter 2.8 ml. oftrimethylsilyldiethylamine is added. After 30 min. another 2.8 ml. oftrimethylsilyldiethylamine is added. After 1.5 hr. the reaction mixtureis cooled to -70° C. and 150 ml. of cooled (-70° C.) diethyl ether isadded. This mixture is then cooled and poured into 100 ml. of ice coldsaturated sodium bicarbonate solution and extracted three times withdiethyl ether. The combined ethereal extracts are then washed with icecold saturated sodium bicarbonate and brine, dried over magnesiumsulfate, and concentrated to yield the formula XLVIII 11-silylatedcompound.

E. As described in part B above, the reaction product of part E isacylated at C-9, yielding the formula XLIX compound.

F. The formula LXIX compound is then dissolved in 25 ml. oftetrahydrofuran and treated with a solution of tetra-n-butyl ammoniumfluoride and tetrahydrofuran. This reaction mixture is then stirred at65° C. for 2 hr. and thereafter cooled to ambient temperature. Theresulting product is then concentrated and the reduced pressure, dilutedwith brine, and extracted with ethyl acetate. The organic extract isthen washed with 2M aqueous potassium bisulfate and brine over magnesiumsulfate. Concentrated under reduced pressure yields the title product.

Preparation 3

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor,15-acetate, 1,9-lactone (Formula LXIX: Z₁ is ##STR86## Y₁ istrans--CH═CH--, M₃ is ##STR87## R₃ and R₄ of the L₁ moiety are hydrogen,and R₇ is phenoxy).

Refer to Chart B and Chart D (Part II).

A. 3,7-Inter-m-phenylene-3-oxa-4,5,6,17,18,19,20-heptanor-PGF₁α,15-acetate (Preparation 2, part C, 35 mg.), 39 mg. oftriphenylphosphine, and 33 mg. of 2,2'-dipyridyldisulfide in 0.5 ml. ofdry oxygen free benzene is stirred at ambient temperature for 18 hr. Themixture is thereafter diluted with 25 ml. of benzene and heated atreflux for 24 hr. Thereafter, pure product is isolated from the reactionmixture employing silica gel chromatographic separation.

Following the procedure of Preparations 2 and 3, each of the variousPGF₆₀ -type compounds of formula XL of Chart B is transformed to a PGF₆₀-9,15-diacylate of formula L or a PGF₆₀ , 15-acylate, 1,9-lactoneformula LXIX.

EXAMPLE 7

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-TXB₁,methyl ester (Formula LXVI: R₁ is methyl, Z₁ is ##STR88## R₆ ishydrogen, Y₁ is trans--CH═CH--, R₃ and R₄ of the L₁ moiety and R₅ of theM₁ moiety are hydrogen, and R₇ is phenoxy).

Refer to Chart D.

A solution of 800 mg. of3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-tetranor-PGF.sub.1α,methyl ester 9,15-diacetate in 32 ml. of dry benzene is treated with1.21 g. of lead-tetraacetate (recrystallized from acetic acid and driedunder reduced pressure over potassium hydroxide) at 50° C. under anitrogen atmosphere. Reaction conditions are maintained for about 70min. The resulting mixture is then filtered through Celite and thefiltrate washed with brine. The process of filtration is repeated andthe second such filtrate is washed with brine, dried over sodiumsulfate, and evaporated under reduced pressure at ambient temperature toyield{m-2-[(1'S)-3'-oxo-1'-hydroxypropyl]-(2S,3R,6R)-3,6-dihydroxy-7-phenoxy-trans-4-heptenephenoxy}aceticacid, methyl ester, 3,6,1'-triacetate, a formula LXII compound.

B. The entire crude reaction product from part A is then dissolved in 16ml. of dry methanol, 2.5 ml. of trimethyl orthoformate, and 175 mg. ofpyridine hydrochloride. This mixture is then stirred over a nitrogenatmosphere for about 60 hr. at ambient temperature. Thereafter about 30ml. of dry benzene is added and the methanol removed by concentrationunder reduced pressure. The resulting benzene-containing solution isthen washed twice with brine, dried over sodium sulfate, andconcentrated, yielding a residue.

This residue is then chromatographed on silica gel, eluting with 50 to75 percent ethyl acetate in hexane. Fractions containing puredimethylacetal of the reaction product of part A are combined, yieldingthe formula LXIII thromboxane intermediate.

C. A solution of 110 mg. of sodium and 10 ml. of dry methanol isprepared under a nitrogen atmosphere and to this mixture is added asolution of 420 mg. of the reaction product of part B and 5 ml. of drymethanol. The resulting mixture is then stirred at ambient temperaturefor 1.5 hr. and thereafter 0.5 ml. of acetic acid is added, followed byaddition of benzene. Thereafter, the methanol is substantially removedby evaporation under reduced pressure. This benzene containing solutionis then washed with brine, dried over sodium sulfate, and evaporated toyield a crude product which is then chromatographed on silica gelelution with two percent methanol and ethyl acetate. Fractionscontaining pure{m-2-[(1'S)-3'-oxa-1'-hydroxypropyl]-(2S,3R,6R)-3,6-dihydroxy-7-phenoxy-trans-4-heptenephenoxy}aceticacid, methyl ester, dimethylacetal are obtained.

D. A mixture of 187 mg. of the reaction product of part C under anitrogen atmosphere is treated with a mixture of 4 ml. of acetic acid, 2ml. of water, and 1 ml. of tetrahydrofuran for about 4 hr. Thereupon,the resulting mixture is stirred at ambient temperature under vacuum forabout one hr. and the mixture then freeze dried and chromatographed onsilica gel eluting with one percent methanol and ethyl acetate. There isthereby obtained3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-11-deoxy-11α-and 11β-methoxy-TXB₁, methyl ester and3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-TXB₁, methylester.

E. A solution of 300 mg. of the reaction product of part B in 5 ml. ofdry methanol under nitrogen is treated at room temperature with 10 ml.of a sodium methoxide solution (120 mg. sodium dissolved in 10 ml. ofmethanol) for 45 min. Then 6 ml. of water is added and stirring iscontinued for 135 min. to hydrolyze the methyl ester. A solution of 2.5ml. of 85 percent phosphoric acid in water is added and some of themethanol is removed at reduced pressure. The aqueous residue is thenextracted with ethyl acetate. The extracts are dried over sodium sulfateand evaporated, yielding a free acid formula LXIV residue.

F. The residue of part E is dissolved in 12 ml. of tetrahydrofuran andtreated with 9 ml. of water and 1 ml. of 85 percent phosphoric acid for4.5 hr. at room temperature for about 35 hr. Thereafter the mixture issaturated with sodium chloride and extracted with ethyl acetate. Theethyl acetate extracts are then washed with brine, dried over sodiumsulfate, and concentrated to a residue. This residue is thenchromatographed on silica gel yielding 11-deoxy-11α- and 11β-methoxy3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-tetranor-TXB.sub.1,and3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-tetranor-TXB.sub.

EXAMPLE 8

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-TXB₁,methyl ester.

Refer to Chart D (Parts I and II).

A. A solution of the reaction product of Preparation 3 is transformed tothe reaction product of Example 7, part C, following the procedure ofExample 7, parts A, B, and C.

B. The title product is prepared following the procedure of Example 7,parts D, E, and F.

EXAMPLE 9

2-Decarboxy-2-hydroxymethyl-TXB₂ (Formula Z₁ is cis--CH═CH--(CH₂)₃ --,Y₁ is trans--CH═CH--, R₅ of the M₁ moiety, R₃ and R₅ of the L₁ moiety,and R₆ are all hydrogen, and R₇ is n-butyl).

Refer to Chart A,

750 mg. of 11-deoxy-11α-methoxy-TXB₂, methyl ester dissolved in 50 ml.of diethyl ether are reacted with 500 mg. of lithium aluminum hydride atroom temperature, with stirring. When the starting material iscompletely consumed (as indicated by thin layer chromatographicanalysis) one ml. of water is cautiously added. Thereafter 0.8 ml. of 10percent aqueous sodium hydroxide is added and the resulting mixtureallowed to stir for 12 hr. Thereupon magnesium sulfate is added withstirring and the stirred mixture then filtered through magnesium sulfateand evaporated to a residue, which contains pure2-decarboxy-2-hydroxymethyl-11-deoxy-11α-methoxy-TXB₂.

Following the procedure of Example 1, part F, the reaction product ofthe preceding paragraph is transformed to the title product.

Following the procedure of Example 9, but employing each of the various11-deoxy-11α- or 11β-methoxy-TXB- or TXB-type compounds described above,there are prepared each of the various corresponding2-decarboxy-2-hydroxymethyl-11-deoxy-11α- or 11β-methoxy-TXB- orTXB-type products.

Following the procedure of Example 7 or 8, but employing correspondingPGF₂α -type compounds in place of the starting material therein, thereare prepared:

11-deoxy-11α-methoxy- or 11β-methoxy-TXB₁ ; TXB₁ ;

13,14-dihydro-11-deoxy-11α-methoxy- or 11β-methoxy-TXB₁ ;

13,14-dihydro-TXB₁ ;

11-deoxy-11α-methoxy- or 11β-methoxy-TXB₂ ;

13,14-dihydro-TXB₂ ;

or their respective 15-epimers and the methyl esters thereof.

Following the procedure of Example 7, but employing a correspondingPGF₆₀ starting material as described above, there are prepared11-deoxy-11α-methoxy-TXB₂ -, 11-deoxy-11β-methoxy-TXB₂ -,11-deoxy-11α-methoxy-TXB₁ -, 11-deoxy-11β-methoxy-TXB₁ -, TXB₂ -, orTXB₁ -type compounds, in free acid or methyl ester form, or the15-epimers thereof, which exhibit the following functionalcharacteristics:

16-Methyl-;

16,16-Dimethyl-;

16-Fluoro-;

16,16-Difluoro-;

17-Phenyl-18,19,20-trinor-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

17-(m-chlorophenyl)-18,19,20-trinor-;

17-(p-fluorophenyl)-18,19,20-trinor-;

16-Methyl-17-phenyl-18,19,20-trinor-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-;

16-Fluoro-17-phenyl-18,19,20-trinor-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-;

16-Phenoxy-17,18,19,20-tetranor-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

16-Phenoxy-18,19,20-trinor-;

16-Methyl-16-phenoxy-18,19,20-trinor-;

15,16-Dimethyl-;

15,16,16-trimethyl-;

16-fluoro-15-methyl-;

16,16-difluoro-15-methyl-;

17-phenyl-18,19,20-trinor-15-methyl-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-15-methyl-;

17-(m-chlorophenyl)-18,19,20-trinor-15-methyl-;

17-(p-fluorophenyl)-18,19,20-trinor-15-methyl-;

16-methyl-17-phenyl-18,19,20-trinor-15-methyl-;

15,16,16-trimethyl-17-phenyl-18,19,20-trinor-;

16-fluoro-17-phenyl-18,19,20-trinor-15-methyl-;

16,16-difluoro-17-phenyl-18,19,20-trinor-15-methyl-;

15-phenoxy-17,18,19,20-tetranor-15-methyl-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-15-methyl-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-15-methyl-;

16-phenoxy- 18,19,20-trinor-15-methyl-;

15,16-dimethyl-16-phenoxy-18,19,20-trinor-;

13,14-Dihydro-;

16-Methyl-13,14-dihydro-;

16,16-Dimethyl-13,14-dihydro-;

16-Fluoro-13,14-dihydro-;

16,16-Difluoro-13,14-dihydro-;

17-Phenyl-18,19,20-trinor-13,14-dihydro-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

16-Methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-Fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-Phenoxy-18,19,20-trinor-13,14-dihydro-;

16-Methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-;

2,2-Difluoro-16-methyl-;

2,2-Difluoro-16,16-dimethyl-;

2,2-Difluoro-16-fluoro-;

2,2-Difluoro-16,16-difluoro-;

2,2-Difluoro-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

2,2-Difluoro-16-(p-fluorophenoxy)- 17,18,19,20-tetranor-;

2,2-Difluoro-16-phenoxy- 18,19,20-trinor-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-;

13,14-dihydro-15-methyl-;

15,16-dimethyl-13,14-dihydro-;

15,16,16-trimethyl-13,14-dihydro-;

16-fluoro-13,14-dihydro-15-methyl-;

16,16-difluoro-13,14-dihydro-15-methyl-;

17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

15,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

15,16,16-trimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

16-(p-fluorophenoxy)-y)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

16-Phenoxy-18,19,20-trinor-13,14-dihydro-15-methyl-;

15,16-Dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-;

2,2-difluoro-15-methyl-15,16-dimethyl-;

2,2-difluoro-15,16,16-trimethyl-;

2,2-difluoro-15-methyl-;

2,2-difluoro-16,16-difluoro-15-methyl-;

2,2-difluoro-17-phenyl-18,19,20-trinor-15-methyl-;

2,2-difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-15-methyl-;

2,2-difluoro-17-(m-chlorophenyl)-18,19,20-trinor-15-methyl-;

2,2-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-15-methyl-;

2,2-difluoro-15,16-dimethyl-17-phenyl-18,19,20-trinor-;

2,2-difluoro-15,16,16-trimethyl-17-phenyl-18,19,20-trinor-;

2,2-difluoro-16-fluoro-17-phenyl-18,19,20-trinor-15-methyl-;

2,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-15-methyl-;

2,2-difluoro-16-phenoxy- 17,18,19,20-tetranor-15-methyl-;

2,2-difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-15-methyl-;

2,2-difluoro-16-phenoxy- 18,19,20-trinor-15-methyl-;

2,2-difluoro-15,16-dimethyl-16-phenoxy-18,19,20-trinor-;

2,2-Difluoro-13,14-dihydro-;

2,2-Difluoro-16-methyl-13,14-dihydro-;

2,2-Difluoro-16,16-dimethyl-13,14-dihydro-;

2,2,16-Trifluoro-13,14-dihydro-;

2,2,16,16-Tetrafluoro-13,14-dihydro-;

2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2,16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy(-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(p-fluorophenoxy(-17,18,19,20-tetranor-13,14-dihydro-;

2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-difluoro-13,14-dihydro-15-methyl-;

2,2-difluoro-15,16-dimethyl-13,14-dihydro-;

2,2-difluoro-15,16,17-trimethyl-13,14-dihydro-;

2,2,16-trifluoro-13,14-dihydro-15-methyl-;

2,2,16,16-tetrafluoro-13,14-dihydro-15-methyl-;

2,2-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-15,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-difluoro-15,16,16-trimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

2,2-difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

2,2-difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetra-nor-13,14-dihydro-15-methyl-;

2,2-difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetra-nor-13,14-dihydro-15-methyl-;

2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-dihydro-15-methyl-;

2,2-difluoro-15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-.

Following the procedure of Example 7 or 8, but employing correspondingstarting material as described above there are prepared11-deoxy-11α-methoxy- or 11β-methoxy-TXB₁ - or TXB₁ -type compounds, infree acid or methyl ester form, or the respective 15-epimers thereof,which exhibit the following functional characteristics;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-methyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-dimethyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-fluoro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16-methyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-;

3,7-inter-m-phenylene-3-oxa-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-inter-m-phenylene-3-oxa-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-methyl-16-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16-dimethyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16,16-trimethyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-fluoro15-methyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3oxa-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenylene-3oxa-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16phenoxy-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-3-oxa-15,16-dimethyl-16-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-methyl-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-dimethyl-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-fluoro-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-trinor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-16-methyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-3-oxa-16-methyl-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16-dimethyl-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-15,16,16-trimethyl-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16-fluoro-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-phenyl-4,5,6,18,19,20-trinor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-3-oxa-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-3-oxa-15,16-dimethyl-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-4,5,6-trinor-;

3,7-Inter-m-phenylene-4,5,6-trinor-16-methyl-;

3,7-Inter-m-phenylene-4,5,6-trinor-16,16-dimethyl-;

3,7-Inter-m-phenylene-4,5,6-trinor-16-fluoro-;

3,7-Inter-m-phenylene-4,5,6-trinor-16,16-difluoro-;

3,7-Inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor;

3,7-Inter-m-phenylene-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-16-methyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-16-phenoxy-17-phenyl-4,5,6,17,18,19,20-heptanor-;

3,7-Inter-m-phenylene-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-Inter-m-phenylene-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-Inter-m-phenylene-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-;

3,7-Inter-m-phenylene-6-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-16-methyl-16-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-Inter-m-phenylene-4,5,6-trinor-15-methyl-;

3,7-inter-m-phenylene-4,5,6-trinor-15,16-dimethyl-;

3,7-inter-m-phenylene-4,5,6-trinor-15,16,16-trimethyl-;

3,7-inter-m-phenylene-4,5,6-trinor-16-fluoro-15-methyl-;

3,7-inter-m-phenylene-4,5,6-trinor-16,16-difluoro-15-methyl-;

3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenylene-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenylene-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-15-methyl-;

3,7-inter-m-phenoxy-4,5,6,18,19,20-hexanor-15-methyl-;

3,7-inter-m-phenylene-15,16-dimethyl-16-phenoxy-4,5,6,18,19,20-hexanor-;

3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-;

3,7-Inter-m-phenylene-4,5,6-trinor-16-methyl-13,14-dihydro-;

3,7-Inter-m-phenylene-4,5,6-trinor-16,16-dimethyl-13,14-dihydro-;

3,7-Inter-m-phenylene-4,5,6-trinor-16-fluoro-13,14-dihydro-;

3,7-Inter-m-phenylene-4,5,6-trinor-16,16-difluoro-13,14-dihydro-;

3,7-Inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-methyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-Inter-m-phenylene-16-methyl-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-4,5,6-trinor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-4,5,6-trinor-15,16-dimethyl-13,14-dihydro-;

3,7-inter-m-phenylene-4,5,6-trinor-15-,16,16-trimethyl-13,14-dihydro-;

3,7-inter-m-phenylene-4,5,6-trinor-16-fluoro-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-4,5,6-trinor-16,16-difluoro13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-17-(m-trifluoromethylphenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-17-(m-chlorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-17-(p-fluorophenyl)-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-15,16-dimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7-inter-m-phenylene-15,16,16-trimethyl-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-;

3,7inter-m-phenylene-16-fluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-16,16-difluoro-17-phenyl-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-16-phenoxy-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-17-(m-trifluoromethylphenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-16-(m-chlorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-16-(p-fluorophenoxy)-4,5,6,17,18,19,20-heptanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-15-methyl-;

3,7-inter-m-phenylene-15,16-dimethyl-16-phenoxy-4,5,6,18,19,20-hexanor-13,14-dihydro-;

5-Oxa-;

5-Oxa-16-methyl-;

5-Oxa-16,16-dimethyl-;

5-Oxa-16-fluoro-;

5-Oxa-16,16-difluoro-;

5-Oxa-17-phenyl-18,19,20-trinor-;

5-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

5-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-;

5-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-;

5-Oxa-16-methyl-17-phenyl-18,19,20-trinor-;

5-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-;

5-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-;

5-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor:;

5-Oxa-16-phenoxy-17,18,19,20-tetranor-;

5-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

5-oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

5-oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

5-oxa-16-phenoxy-18,19,20-trinor-;

5-oxa-16-methyl-16-phenoxy-18,19,20-trinor-;

5-oxa-15-methyl-5-oxa-15,16-dimethyl-;

5-oxa-15,16,16-trimethyl-;

5-oxa-16-fluoro-15-methyl-;

5-oxa-16,16-difluoro-15-methyl-;

5-oxa-17-phenyl-18,19,20-trinor-15-methyl-;

5-oxa-17-(m-trifluoromethylphenyl)18,19,20-trinor-15-methyl-;

5-oxa-17-(m-chlorophenyl)-18,19,20-trinor-15-methyl-;

5-oxa-17-(p-fluorophenyl)-18,19,20-trinor-15-methyl-;

5-oxa-15,16-dimethyl-17-phenyl-18,19,20-trinor-;

5-oxa-15,16,16-trimethyl-17-phenyl-18,19,20-trinor-;

5-oxa-16-fluoro-17phenyl-18,19,20-trinor-15-methyl-;

5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-15-methyl-;

5-oxa-16-phenoxy-17,18,19,20-tetranor-15-methyl-;

5-oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-15-methyl-;

5-oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-15-methyl-;

5-oxa-16-phenoxy-18,19,20-trinor-15-methyl-;

5-oxa-15,16-dimethyl-16-phenoxy-18,19,20-trinor-

5-oxa-13,14-dihydro-;

5-oxa-16-methyl-13,14-dihydro-;

5-oxa-16,16-dimethyl-13,14-dihydro-;

5-oxa-16-fluoro-13,14-dihydro-;

5-Oxa-16-fluoro-13,14-dihydro-;

5-Oxa-16,16-difluoro-13,14-dihydro-;

5-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-;

54-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

5-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

5-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

5-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

5-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

5-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

5-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

5-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

5-oxo-16-(m-chlorophenoxy)-17,18,19,20-tetranor-15-methyl-;

5-oxa-16-pheoxy-18,19,20-trinor-15-methyl-;

5-oxa-15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;

5-oxa-13,14-dihydro-15-methyl-;

5-oxa-15,16-dimethyl-13,14-dihydro-;

5-oxa-15,16,16-trimethyl-13,14-dihydro-;

5-oxa-16-fluoro-13,14-dihydro-15-methyl-;

5-oxa-16,16-difluoro-13,13-dihydro-15-methyl-;

5-oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-15,16-dimetyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-oxa-15,16,16-trimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

5-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

5-oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

5-oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

5-oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-15-methyl-;

5-oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-15-methyl-;

5-oxa-15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

EXAMPLE 10

TXB₁ 15-epi-TXB₁, 11-deoxy-11α-methoxy-TXB₁,15-epi-11-deoxy-11α-methoxy-TXB₁, 11-deoxy-11α-methoxy-TXB₁, methylester, or 15-epi-11-deoxy-11α-methoxy-TXB₁, methyl ester.

Refer to Chart A (Part VI).

A. The formula XXXIV compound wherein R₃₄ is benzyl and R₃₃ is methyl(1.7 g.) dissolved in 17 ml. of toluene and 4 ml. of tetrahydrofuran iscooled under an argon atmosphere in a dry-ice acetone bath. To thiscooled solution is added diisobutylaluminumhydride. The reaction iscomplete in about 30 min., and the reaction mixture is thereaftertreated at -78° C. with 1.7 ml. of water (added dropwise) and allowed towarm to 25° C. The resulting mixture is then filtered and the solidwashed with benzene. The combined filtrates are then washed with brineand the organic layer dried over magnesium sulfate. Concentration of thesolution under reduced pressure yields 1.71 g. of a formula XXXVresidue, which solidifies on standing. Silica gel TLC R_(f) is 0.13 inethyl acetate and Skellysolve B (40:60).

B. Sodium hydride (55 percent dispersion in oil), 2.9 g, is washed withn-hexane. To the residue is added 43 ml. of dry dimethylsulfoxide andthe mixture heated to 65° C. for 2 hr. under an argon atmosphere. Aresulting dark gray mixture is then cooled to 15° C. and maintained atthat temperature while 15.4 g. of 4-carboxybutyltriphenylphosphoniumbromide, dissolved 70 ml. of dry dimethylsulfoxide, is added during 15min. The resulting mixture is then allowed to warm to 25° C. and stirredfor one hr. The mixture is then cooled again to 15° C. and treated overa 10 min. period with 1.71 g. of the reaction product of part A above,dissolved in 13 ml. of dry dimethylsulfoxide. After one hr., 300 mg. ofwater is added while maintaining the reaction temperature below 20° C.The resultant mixture is then extracted with diethyl ether and theaqueous layer treated with 50 g. of ammonium chloride in 100 ml. ofsaturated brine. The resulting mixture is then extracted with ethylacetate and the ethyl acetate layer dried over magnesium sulfate andconcentrated under reduced pressure. the residue thusly obtained in thentreted with excess ethereal diazomethane. The diethyl ether is thenevaporated and the residue chromatographed over 200 g. of silica gel.Eluting with mixtures of ethyl acetate and Skellysolve B (40:60 and50:50), pure formula XXXVI product wherein R₁ is methyl, g is one, R₂ ishydrogen, R₃₃ is methyl, and R₃₄ is benzyl, 2.02 g., is obtained. NMRabsorptions are observed at 1.4-2.5, 3.35, 3.62, 4.58, 4.8-5.0, 5.2-5.6,and 7.3 δ. The mass spectrum indicates a parent peak 360.1929. Silicagel TLC R_(f) is 0.41 in ethyl acetate and Skellysolve B (40:60).

C. The reaction product of part B (2.02 g.) is dissolved in 200 ml. ofethyl acetate. Thereafter 2 g. of a 5 percent palladium-on-carboncatalyst is added and the mixture hydrogenated at 40 pounds per squareinch. Hydrogen uptake is monitored, and after 3 hr. an additional 2 g.of a 5 percent palladium-on-charcoal catalyst is added. Hydrogenation isthen allowwed to continued for 16 hr. whereupon an additional 2 g. ofthe above catalyst is added and the reaction conditions are maintainedfor an additional 24 hr. At this point, silica gel TLC indicates thereaction is complete and the catalyst is removed by filtration and thesolvent evaporated under vacuum yielding 1.51 g. of the formula XXXVIIproduct as an oil. NMR absorptions are observed at 0.8-2.1, 2.1- 2.5,2.8-3.2, 3.67, 3.5-4.2, and 4.8-5.0 δ. Infrared absorptions are observedat 3600, 2900, 1740, 1430, 1180, 1120, and 1050 cm.⁻¹. The mass spectrumindicates a parent peak at 417.2492. Silica gel TLC R_(f) is 0.9 inethyl acetate and Skellysolve B (40:60).

D. The reaction product of part C (1.51 g.) and 3.08 g. ofdicyclohexylcarbodiimide are dissolved in 21 ml. of benzenne and theresulting solution stirred at 25° C. under an argon atomsphere. To thissolution is then added 2.48 g. of one M phosphoric acid indimethylsulfoxide. After 90 min. the reaction mixture is treated with1.5 g. of oxalic acid, dissolved in 3 ml. of methanol. The resultingmixture is then stirred, such stirring continuing until about 15 min.after an initial vigorous bubbling has ceased. The mixture is thenfiltered and the collected solids washed with benzene. The combinedbenzene solutions are then washed with a 5 percent sodium bicarbonatesolution, dried over sodium sulfate, and evaporated under reducedpressure to yield a crude formula XXXVIII aldehyde, as an oil.

This oil is then dissolved in 15 ml. of diethyl ether and the resultingsolution treated with 33 ml. of 0.3 M tri-n-butyl-2-oxoheptylidinephosphorane and diethyl ether. After 1.5 hr. the reaction mixture isdiluted with diethyl ether and resulting solution is washed with one Naqueous hydrochloric acid 5 percent aqueous sodium bicarbonate, anddried over magnesium sulfate. Concentration of the solution underreduced pressure yields crude 11-deoxy-11α-methoxy-15-dehydro-TXB₁,methyl ester, as an oil. This product is then chromatographed over 200g. of silica gel, eluting with acetone and benzene (7:93), yielding 1.15g. of pure product.

Silica gel TLC R_(f) for the formula XXXVIII compound is 0.27 in acetoneand benzene (10:90).

For the 15-dehydro-TXB₁ reaction product NMR absorptions are observed at0.7-2.7, 3.35, 3,63, 4.8-4.95, 6.32, and 6.85 δ. Infrared absorptionsare observed at 3600, 2900, 1740, 1675, 1450, 1430, 1360, 1180, 1120,1150, and 1020 cm.⁻¹. The mass spectrum exhibits a parent peak at366.2406. Silica gel TLC R_(f) is 0.32 in acetone and benzene (10:90).

E. Dry zinc chloride (1.89 g.) is added to 25 ml. of drytetrahydrofuran, and the mixture is stirred under an argon atmosphere atambient temperature. To this mixture is added 0.5 g. of sodiumborohydride. After 24 hr. this mixture is cooled to -20° C. and treatedwith 1.15 g. of the reaction product of part D in 10 ml. of drytetrahydrofuran, the addition proceeding over 5 min. After 2 hr. at -20°C. the reaction is allowed to warm to ambient temperature and stirred 5additional hr. The excess reducing agent is then destroyed by thecareful addition of water. The reaction mixture is then poured intomethyl acetate and extracted with brine, water, 5 percent aqueous sodiumbicarbonate, and again with brine. The organic layer is then dried overmagnesium sulfate and concentrated under reduced pressure yielding 1.12g. of crude 11-deoxy-11α-methoxyTXB₁, methyl ester, and its 15-epimer.The epimeric alcohols are then purified by silica gel chromatographed,eluting with mixtures of acetone and benzene (5:95 to 20:80).Accordingly, there are obtained 479 mg. off the 15-epi compound and 536mg. of (15S) compound. For the 15-epi alcohol NMR absorptions areobserved at 0.65-2.5, 3.53, 3.63, 3.7-4.3, 4.7-4.95, and 5.6-5.85 δ. Themass spectrum exhibits a parent peak 544.3598. Silica gel TLC R_(f) is0.19 in acetone and benzene (10:90).

For the (15S) compound NMR absorptions are identical to those observedfor the 15epi compound. The high resolution mass spectrum exhibits aparent peak at 544.3608. Silica gel TLC R_(f) is 0.14 in acetone andbenzene (10.90).

F. The 15epi reaction product of part E (400 mg.) in 400 ml. of 45percent aqueous potassium hydroxide are dissolved in 12 ml. of methanoland the resulting solution stirred at ambient temperature under an argonatmosphere for 15 min. The resulting mixture is then diluted with waterand saturated sodium chloride. The resulting solution is then acidifiedto pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. Theethyl acetate extracts are then washed with brine, dried over magnesiumsulfate, and evaporated under reduced pressure yielding 372 mg. of pure11-deoxy-11α-meethoxy-15-epi-TXB₁. NMR absorptions are observed 3.36,3.8- 4.3, 3.75- 3.95, and 5.4-5.9 δ. The mass spectrum exhibits a parentpeak at 602.3854. Silica gel TLC R_(f) is 0.14 in acetone and benzene(40:60) and 0.73 in the A-IX solvent system.

G. The reaction product of part F (365 mg.) and 0.18 ml. of 85 percentphosphoric acid are dissolved in 2.2 ml. of tetrahydrofuran and 1.8 ml.of water. The resulting solution is then warmed to 40° C. for 10 hr. Thereaction mixture is then cooled and diluted with ethyl acetate andbrine. The various layers are then separated and the aqueous layerextracted with ethyl acetate. The combined ethyl acetate solutions arethen washed with brine, dried over magnesium sulfate, and evaporatedunder reduced pressure. The resulting residue is chromatographed on 30g. of silica gel, eluting with ethyl acetate and Skellylosolve B (75:25)and ethyl acetate, yielding 273 ml. of 15-epi-TXB₁. Infrared absorptionsare observed to 3350, 2900, 1710, 1370, 1240, 1100, 1040, 1070, 1020,and 970 cm.⁻¹. The mass spectrum exhibits a parent peak at 645.3860.Silica gel TLC R_(f) is 0.50 in A-IX solvent system.

H. Following the procedure of part F, 400 mg. of the reaction product ofpart E is transformed to 11-deoxy-11α-methoxy-TXB₁. The NMR absorptionsare observed at 3.38, 4.75-4.95, and 5.3- 6.1 δ. The mass spectrumexhibits a parent peak 602,3851. Silica gel TLC R_(f) is 0.22 in acetoneand benzene (40:60) and 0.71 in the A-IX solvent system.

I. The reaction product of part 8 (370 mg.) is transformed to TXB₁following the procedure described in part G above. Infrared absorptionsare observed at 3400, 2950, 2875, 1715, 1240, 1110, 1040, 1020, and 970cm.⁻¹. The mass spectrum exhibits a parent peak at 660.4087. Silica gelTLC R_(f) is 0.46 in the A-IX solvent system.

We claim:
 1. A thromboxane analog of the formula. ##STR89## wherein R₆is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein M₁ is##STR90## wherein R₅ is hydrogen or methyl; wherein L₁ is ##STR91##wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same ordifferent with the proviso that one of R₃ and R₄ is methyl only when theother is hydrogen or methyl;wherein Y₁ is trans -- CH═CH-- or --CH₂ CH₂-; wherein R₇ is ##STR92## wherein 1 is zero, one, two, or three;wherein m is one to 5, inclusive, T is alkyl of one to 3 carbon atoms.inclusive, alkoxy of one to 3 carbon atoms, inclusive, chloro, fluoro,or trifluoroethyl, and s is one, two, or 3, the various T's being thesame or different, with the proviso that not more than two T's are otherthen alkyl, with the further proviso that R₇ is ##STR93## only when R₃and R₄ are hydrogen or methyl, being the same or different; wherein Z₄is (1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, (2cis--CH═CH--CH₂--(CH₂)_(g) --CF₂ --, (3) cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --, (4)--(ch₂)₃ --(ch₂)_(g) --CH₂ --, (5) --(ch₂)₃ --(ch₂)_(g) --CF₂ --, (6)--ch₂ --o--ch₂ --(ch₂)_(g) --CH₂ --,wherein g is one, or 3; and whereinX₁ is (1) --CH₂ OH, or (2) --COOR₁, wherein R₁ is alkyl of one to 12carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive,aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substitutedwith one or two chloro, fluoro, or alkyl of one to 4 carbon atoms,inclusive, or a pharmacologically acceptable cation, with the overalproviso that Z₄ is cis--CH═CH--(CH₂)₃ --Y₁ is trans--CH═CH--, R₃, R₄,and R₅ are all hydrogen, and R₇ is n-butyl, only when X₁ is --CH₂ OH. 2.A thromboxane analog according to claim 1, wherein R₆ is alkyl of one to4 carbon atoms, inclusive.
 3. 11-Deoxy-11α-methoxy-TXB₁, a thromboxaneanalog according to claim
 2. 4. A thromboxane analog according to claim1, wherein R₆ is hydrogen.
 5. A thromboxane analog according to claim 4,wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ --.
 6. 2,2-difluoro-TXB₁ athromboxane annalog according to claim
 5. 7. A thromboxane analogaccording to claim 4, wherein Z₄ is cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂--.
 8. 2,2-Difluoro-TXB₂, a thromboxane analog according to claim
 7. 9.A thromboxane analog according to claim 4, wherein Z₄ is cis--CH₂--CH═CH--(CH₂)_(g) --CH₂ --.
 10. cis-4,5-Didehydro-TXB₁, a thromboxaneanalog according to claim
 9. 11. A thromboxane analog according to claim4, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g--CH) ₂ --.
 12. TXB₁, a thromboxaneanalog according to claim
 11. 13. A thromboxane analog according toclaim 4, wherein Z₄ is --(CH₂)₂ --O--(CH₂)_(g) --CH₂ --.
 14. 5-Oxa-TXB₁,a thromboxane analog according to claim
 13. 15. A thromboxane analogaccording to claim 4, wherein Z₄ is cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂--.
 16. A thromboxane analog according to claim 15, wherein X₁ is --CH₂OH.
 17. 2-Decarboxy-2-hydroxymethyl-TXB₂, a thromboxane analog accordingto claim
 16. 18. A thromboxane analog according to claim 15, wherein X₁is --COOR₁.
 19. A thromboxane analog according to claim 18, wherein M₁is ##STR94##
 20. 15-epi-15-Methyl-TXB₂, a tjromboxane analog accordingto claim
 19. 21. A thromboxane analog according to claim 18, wherein M₁is ##STR95##
 22. A thromboxane analog according to claim 21, wherein R₇is ##STR96##
 23. 17-Phenyl-18,19,20-trinor-TXB₂, a thromboxane analogaccording to claim
 22. 24. A thromboxane analog according to claim 21,wherein R₇ is ##STR97##
 25. 16-Phenoxy-17,18,19,20-tetranor-TXB₂, asthromboxane analog according to claim
 24. 26. A thromboxane analogaccording to claim 21, wherein R₇ is --(CH₂)_(m) --CH₃.
 27. Athromboxane analog according to claim 26, wherein m is
 3. 28. Athromboxane analog according to claim 27, wherein g is
 3. 29.2a,2b-Dihomo-TXB₂, a thromboxane analog according to claim
 28. 30. Athromboxane analog according to claim 29, wherein g is one.
 31. Athrombonxane analog according to claim 30, wherein Y₁ is --CH₂ CH₂ --.32. 13,14-Dihydro-TXB₂, a thromboxane analog according to claim
 31. 33.A thromboxane analog according to claim 30, wherein Y₁ istrans--CH═CH--.
 34. A thromboxane analog according to claim 33, whereinR₅ is methyl.
 35. A thromboxane analog according to claim 34, wherein atleast one of R₃ and R₄ is fluoro.
 36. A thromboxane analog according toclaim 35, wherein R₃ and R₄ are both fluoro. 37.15-Methyl-16,16-difluoro-TXB₂, methyl ester, a thromboxane analogaccording to claim
 36. 38. 15-Methyl-16,16-difluoro-TXB₂, a thromboxaneanalog according to claim
 36. 39. A thromboxane analog according toclaim 34, wherein at least one of R₃ and R₄ is methyl.
 40. A thromboxaneanalog according to claim 39, wherein R₃ and R₄ are both methyl. 41.15,16,16-Trimethyl-TXB₂, methyl ester, a thromboxane analog according toclaim
 40. 42. 15,16,16-Trimethyl-TXB₂, a thromboxane analog according toclaim
 40. 43. A thromboxane analog according to claim 34, wherein R₃ andR₄ are both hydrogen.
 44. 15-Methyl-TXB₂, methyl ester, a thromboxaneanalog according to claim
 43. 45. 15-Methyl-TXB₂ a thromboxane analogaccording to claim
 43. 46. A thromboxane analog according to claim 33,wherein R₅ is hydrogen.
 47. A thromboxane analog according to claim 46,wherein at least one of R₃ and R₄ is fluoro.
 48. A thromboxane analogaccording to claim 47, wherein R₃ and R₄ are both fluoro. 49.16,16-Difluoro-TXB₂, methyl ester, a thromboxane analog according toclaim
 48. 50. 16,16-Difluoro-TXB₂, a thromboxane analog according toclaim
 48. 51. A thromboxane analog according to claim 46, wherein atleast one of R₃ and R₄ is methyl.
 52. A thromboxane analog according toclaim 51, wherein R₃ and R₄ are both methyl.
 53. 16,16-Dimethyl-TXB₂,methyl ester, a thromboxane analog according to claim
 52. 54.16,16-dimethyl-TXB₂, a thromboxane analog according to claim 52.